The Molecular Cell Biology

7/31/2019 The Molecular Cell Biology

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u ReI'. mmul gh < / ! vw ll gh v

THE MOLECULAR CEL BIOLOGY

OF INTRFRON-y AND IS

RCPTOR

Michael A. Farrar and Robert D Schreiber

Deparen f Pay, Wasinn niversiy Sc f Medicine,S Luis Mssuri 6 1

KY WS: FN FN ee te t efee t

Abstract

Te as en years ave seen an expsive rw n ur undersandin f

FN" Te nin f e cDNs fr FN and s recepr ave madeavaiabe are auns f iy puried recbinan FN and subeFN recepr n addiin, iy specic neuraizin mncna anibdies ave been eneraed b f ese preins . sin ese reaensFN and e FN recepr ave been caracerized n a ecuar basisSrucuefncin sudies carried u n ese preins ave idenied keyecuar reins a are reuired fr biic acviy. Mrever, a readea s nw knwn cncernin e pysc re a FN pays invv. n is review we fcus n e new devepmens n e areas fFNbceisry and biy and pay paricuar aenn e FN receprand ree aspecs f FN biy a are f specia ineres iuniss s defense, inaain, and auuny

OO

nerfernaa (FN was rs recnized neary years a n ebasis f is anivira aciviy (1 ) . Durin e ensun years, a rea dea f

infrmai as acumuaed wic unequivay esabises a sperpic cykine pays an impran re in mduaing neary a pasesf mmune and inamary respnses. Durin e pas 1 years, eenes fr FN and is reepr ave been cned and e srucures f

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5 FAA & SCIB

te rresndn rtens deterned Lare aunts f ly uredrebnant F and F reetr are nw avalable as well as neutraln nlnal antbdes se fr eter te ytkne r ts reetr Te avalablty f tese reaents as faltated any studes aed

at eludatn Fs eans f atn at te leular level anddenn ts ysl rle n vv rnally, te nfratn dervedfr years f F resear nw nts t te reatvely nr ysl rtane tat F as as a dret antvral aent n te urrentrevew we fus n se f te re reent develents n te areas fF bestry and bly, and we ae artular eass n wrknernn te F reetr

THE RELATIONSHIP BETWEN IFNy AND OTHERINTRFERONS

F belns t a faly f rtens related by ter ablty t rtet ellsr vral netn Based n several rtera, te nterferns ave beendvded nt tee dstnt lasses tered nterfern, , and (Table 1) F (rnally knwn as Tye F r Leukyte F beause twas rdued by erera bld nnulear ells and F (alsnally knwn as Tye F r Fbrblast F beause f ts ell f

rn are lassal nterferns ndued n resnse t vral nfetn fells (, ) Twenty sx F enes (nludn several seudenes avebeen dented 4). Te enes ave n strutures, e tey lakntns and aear t derve fr a n anestral reursr 5)Te F ene luster resdes n uan rse 9 and urnerse 4 6) Ts ene faly endes at least dstnt rtensw ae snle lyetde ans f 1 651 66 an ads wt leularwets arxately kDa (. Te reasns fr te lexty fte F ene syste rean unear, but reent studes suest tat tederent F sees eet dstnt arrays f bla resnses nderent els ( Tere s nly a snle fr f F t s ended by adstnt ene lated next t te F lus n bt uan and useBased n te eneral ranatn f ter enes and rtens, F andF are tut t ave evlved fr a n anestral reursrHweve F sares nly lted anten relatedness t te Faly, and te rtens dslay ny 15% an ad sequene ly ) everteless, bt frs f Tye F bnd t te sae

reetr n te surfae f susetble taret ells, ndatn tat at leastse f te funtnally rtant rens f te leules ave beennserved ltu an earler rert suested te exstene f a sendF sees, desnated F (8) subsequent studes revealed tat te


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b roertie o te interferon

oety

NOMENCATURE

MAOR INDCERS

HSICA ROERTIESM D

reice/teAmino ciNine glycoyltionSbnit comiion

H tbilityGENE STRCTURE

FN

Tye I

eocyeVir

0/06566Some ecieSinge

olyetie

Stble

Nber of gee 6Cromool octon

Mrine Hmn 9

reence of intron None

CEUAR SOURCE T cell B cell n

CEUAR RECETORM (D)reicemtre

Amino ciDoin rcte

EtrcellTrnmebnentcelllr

Glycoylion iteCromooml locion

MineHmn

mco ge

605950050

09

00

6

I A RO

IFN

Tye I

FbrobVir Soly RNA

0/05 66

+Single

olyetie

Stble

9None

Fiboblt nei telil cell

6

IFN

Tye II

mneAntigenMitogen

/50 ieNoncovent

ooier

bile

0

T cell nN cell

5685957

8

5

06

bserved avty was ascrbabe L-6 wc eced anvra respnsesn ceran n vr assays n an ndrec manner 9, 1 0

N as ermed Type N r mmune N s unreated t teype nterferns a b te enetc and e prten eves 1 1 1Mrever, FN s nduced by a unue se f stmu and s prduced ny

by T ympcyes and naura ker N ces mprany, vra nfectnf tese ces ds nt drecty nduce FN prducn Au FNdspays ms f te bc actves a ave been ascrbed te ternerferns as a 1 0- 100 fd wer specc anvra actvty tan eer


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54 AA & SCB

FN r FN On te er and, FN is 1 -1 , ties re activeas an iunduatr an are er casses f nterferns (14 isbservain as ead te cncep ta wereas FN are priariyanivira aens wic dispay se iunduary aciviy, FN is

priariy an iunduatr at as can exer se antivra activty(5.

MOLCULAR CHARACTRIIC OF UMAN ANDMURIN IFNy

e cDNAs fr uan and urine FN were rst cned n 198 byGray & Gedde (-3, and day a rea dea is knw abu esrucure f e FN enes and e crrespndin preins tey encdeBt uans and ice cntain y a sne FN ene. e FN eneis cnsideraby re cpex an e enes fr eiter FN r FNe uan and urine enes are 6 kb in size, and eac cnains furexns and tree inrns. sin in situ ybridizain tecniues, e enesfr uan and urine FN ave been caized t uan crse2 (2241 and urine crse , respecivey (6, 6, ereuary eeens n e FN ene ave been ny pariay caracerized A issuennspecic enancer eeen as been deeced in a

bp seuence witin e rs inrn f e uan ene (18. siive andneatve acn prer eeens ave been idenied in a rein bp edatey 5 e ranscriptin sar site (18, 19 e seuencesin e prer respnsibe fr issuespecic ene expresin reainunknwn. nteresny, wen DNA cntainin te entre uan FNene and 2.3 and kb f 5 and 3 ankin enoic seuence, respectivey, was nrduced in te urine er ne, te resuin transenicice dispayed inducbe expressn f uan FN n a issue apprprateanner (. n cnras, wen e uan ene was inrduced n avariey f dieren cuured urine ce ines (suc as ce and brbass, e ssue speciciy f expressin was s (2, 22 us, abeen suesed at reuatin f FN ene expressin us as dependn as ye undened devepenta factrs

Acivain f e uan ene eads e enerain f a 1 . kb RNAa encdes a 66 an acid pypepde ( , 23. e ain erina23 residues f e uan prein cnsiue a ypica ydrpbic sinaseuence wic, wen prteyicay reved, ives rise a aure 143

residue psiivey cared pypeptide wi a predicted ecuar ass f1 kDa (Fiure 1 Au te ain erinus f e aure pypepidewas riinay prediced be ysyrys ( an erina seuencanaysis perfred n naura frs f uan FN densrated ta


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-23

F A IF RCOR

10

Fgure Scemtic ereentton o te umn FN molecule FN yntee 6 mno ci olyetie tt contin mino ci ignl euence (eignte in tee bo Te mure otein contin mno ci Te locion of e wo Nlinkeglycoylion ite noe A unctionlly imortnt region o te molecule been meto te mno emnl 9 eiue n ton econ motnt regon been locle tote crboy termnl 5 reiue To FN olyete elocite to orm noncovlenomome

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6/41

6 FARRAR & SCRBR

e aino erinus was actuay pyoutaic acid (Fiue I (4 ecarboxy terinus of te oecue is susceptibe o posransaiona enyatic deradation (4 east six dieren carboxy teini ave beendetected on natua and recobinant fos of uan IFN. ince is

poion of e oecue contains a are nuber of posivey caredresidues, e various truncaions conribute to e cae eeoeneityseen in e fuy aue oecue. wo poypepides sefassociae o foa oodie wi an apparen oecua wei of 34 kDa (2-3 tpysiooic concentaions, ie if any onoe is detecabe Ony tedier can dispay FN biooic activiy, possiby because i is e onyfor of te oecue tat can eect FN receptor dierization (3 1 , 3 1 a,3. Since e aue uan N poypepide is devoid of cyseine, teoodier is ed toeter entiey by noncovaent foces e uaenay

sucure of te oecue expains is caraceisic sensitivity to exeesof eat (e protein is denaued at epeaues above 6, and pH(activity is apidy ost at pH vaues ess tan 4 and reate tan 9(33-3

e urine ene ives rise to a 1 kb RN tat encodes a ature1 34 aino acid poypepide wit a pediced oecua ass of 1 4 kDa(13 Like is uan counterpart, urine FN exiss excusivey as anoncovaen oodie. Huan and urine IFN dispay ony odest

oooy a eite e cDN o aino acid eves (6% and 4% espectivey is ow eve of seuence oooy expains wy te uan andurine proteins dispay a sic species specicity in eir abiiy to bindto and acivae uan and urine ces.

e individua uan and urine poypepide cains conain wo Ninked ycosyation sies (residues and 9 in aue uan IFNand esidue 16 and 69 in te aue for of urine FN tat areindependeny and dieentiay ycosyaed, teeby ivin rise to subunits of diein oecuar weits. Natua uan IN is coposed ofpoypeptides a dispay oecuar asses of , , and kDa, wiccorresond to oecues wi or bo ycosyaion sites occupied(38, 39. is dieenia ycosyation accounts for uc of te observedoecuar weit eeroeneity in e fuy aue oodieric oecues(i.e . naura uan and urine IFN dispay oecuar weis ta ranefro 3 kDa. Weeas ycosyation is no ipotan fo expessionof FN acivity it appeas o inuence e cicuatoy afife of teoecue (38, 4, 4 1 .

e funcionay iporan reions of te FN oecue are now beineucidated uen data indicae tat bot e aino and carboxy einaeions pay critica oes in ainainin an acive conforaion of tepoein e ipotance of te aino terina reion as been docu


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N AND IFN RECEPTOR

mnd by vl ndpndn d nclnl nbd pcc fmn mnl pn f mn nd mn FN blck bndng fFN clll cp nd nl IFN bl ndc nvlcv n bbl nd cv nnpcc cycdl cv n mc

pg (426). n ddn ync ppd w nc cpnd mn mnl 3 mn cd f mn FN bn wn blck bndng f FN cll fc wn ppld ng cncnn (44 4) Fnll mn nd mn FN mlcllckng 1 0 mn mnl d (pdcd by nymcdgn f mlcl w Saphylcccu aueu V-8 p47 48 ng mc gnc ppc4 4) dvd fblgc cvy. O d v pvdd vdnc f n mpnl f cbx mnl pn f mlcl. Alg mvlf cbxy mnl mn cd fm mn FN l n ll n dcn n blgc cv nymc mvl f d 1214 f pn w v ndp c clpn bmxll p0 ypn pn28 0) l n l fld dcn n IFN pcc cvy ( dmnd by mnngFNdpndn ndcn f nvl cvy n bbl nd Fc cp xpn n mnncl pgcy). n ddn nymcllncd fm fFN dpl fld dcn n cp bndng

ny (0). A ncd fm f mn IFN gnd by plcng p cdn f d 12 l wd ml dcn n cpc bnd IFN cp nd ndc IFNdpndn clllpn (1 ). nlly cn mncln nbd cv wcbx mnl ppd f mn (3) nd mn (4) FN nl pn nvl cvy

Rcnly xy cyllgpc c f mn IFN w lvd 3 A () (Fg 2). T dy cnmd dmc n f m pn. T ndvdl bn v nd pl llpclp Hwv vll c f dm cmpc nd glbl mlcl pp b pml lcl 62%) nd lck c. c bn cn f x lc ld g by nnlcl gn T dm fmd by n nwnng f lc c bn fc wc pvd n ppny f mlplncn lng c bn. p f nm bn ncn xm n nd bn n n ny fw pn.T mdl pdc bn c n n n plll fn

by ldng xpn f mn nd cbxy mnlpn f ppng plyppd cn W mn mncdn v bn mly bd cbx mn d ndp gd cnfmn n ln dmnd ng x


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A

B

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Rev.Immunol.1993.11:571-611

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9/41

F A IF RCP 7

ray crysallgrapic r nclear magneic resnance appraces (6, 6a)evereess, e mel sggess a eac imer may be able bind w N receprs. xperimenal aa recenly bained sppris pssibily (3 1 , 3 1 a, 32)

INy BIOSYNHSIS

n e nrma s e T lympcye represens e mar celar srcef N Al CD8+ T ce pplans an cerain sbses fCD4 T celscan prce e prein (7, 8) (igre 3). syness as beenemnsrae n e T elper T cell sbse, an daa as als beenbained ndicaing a i may be prce by a less dereniaecved ye of C T ce desged THO (59-61). Te xrnal sma nce N prcn by T cells are smlar se a ndceer T cell-derived cyknes (7, 8, 62) Te rimary pysigic sims is angen in e cnex f eier mar scmpaibiy (MHC)cass (fr CD4 + T cells) r MHC class anigens (fr CD8+ T cells)xperimenay, N can als be indce by eier (1) irec simlainf e T cel receprCD3 cmpex w anbdies sc as aniCD3, (2)T cell migens (sc as cncanavaln A r pyemagglinin) r (3)parmaclgc sim (sc as e cmbinain f prbl myrisae

aceae and cacm npre) (6) n addiin T ce-depenen prdcn f N is enanced by prcs f acvae T cells an macrpages sc as L2, ydrgen perxide, and ekrienes LTB, L TC4,and LTD4 (64-6) Simain f T cels resls in e incin f mRNA wc is rs deecable a 6-8 rs, peaks by 12-24 rs,and slwly declines ereaer. Te pren is secree immediaely aersyness. can rs be eeced in e exracelar envirnmen 8-12rs aer simlan and reaces peak levels afer 18-24 rs Nprdced as a resl f experimenal n vr T cel simlan (sc asdring e mxed ekcye reacin) is n signicanly cnsmed by ecells f e clre and erefre can be deeced in e meim lng afere T cell acvain respnse as ene (70) n cnras, is rarelyseen n e irclain f mans r mice nderging mmnlgic smlain. Tis apparen discrepancy beween in vr an in vv evels f

Fure Str vw t man N mm a v m nat btan

fr t xray rytagac anay f t rt ya tt a bn vt 35 angtm bbn awng a ba n tn Panl A vw arxmaty aa t t m twf ax. Pan B: vw axmaynar w-f ax c by nt bn ab (Rrn w rn fm a t a (55))

Annu.R

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58 FARRAR & SRIBR

id p FN i m likl d rpid rmvl f FN frm ciclin b FN rcpr r biil xprd n nrlll cll (7 1 )

Tw nwl dcribd cyki r wr i ir rpciv bili

i rgl FN prdcin in ir piiv r ngiv mnnr.L12 (frmrly clld NK imlr fcr NKSF) i prdc f Bcll nd mcrpg nd indc FN gn xprin in T cll ndN cll in mnnr i l rill diinc frm cnvninlwy fT cll civin (72 7. L12 dndn FN indcin iinniiv cyclrin nd i ynrgiic wi ymgglininrbl r niCD L2 nd llgnic nign b n C +inpr (74). T prci imli ld L-12 indcin in vivr n crcrid On r d nr nwl dcrbd

ckin L-l inhibits FN prdci by T cll (7 76) T iibir c f Ll FN prdci r mr prfnd n cn prdci f r T ckin c L-2 L l i prdcdby T 2 CD4 T cll b wll B cll nd mcrpg (77)T mcnim by wic Ll xr i inibiry c n FN

PRODUCING CELL TYPE

CD8+ T CLL

(CTL)

NTRACTON

+Ag

FNy

MHC uAPC TH

e_N

TargetCTL

microbial _ mrobal productpathogen -

NK CLL . FNy

M cophgeTNF

NK Cll

ure euar rce I FN IFN ca be prduced either by D4+ ce i repet aige preeted i the cet ca mece r by cyttic ymphcyteig recgii atge acitd ith ca . additi, NK ce eabrateIFN aer expure t NF ad mcra prduc

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F A IF RECEPTOR 8

prdcn nly nw beng elcded Hwever, e rge L-cn cery e ngen preenng cell nd n e cel (78). ecrren ype IL-l my nb e expren ACdevedccery mlecle reqred ndce cvn e cell r

FN prdcne recen de ve demnred FN cn l be prdcedby nl kller cell (NK) (8) gen cn ndce IFN rmppln mn nd mrne NK cell expnded n v w L2.Hweve, r greer mprnce e bervn bcer ndrmcrbl prdc cn rpdly me FN prdcn rm nve NKcell ppn eer n v r n vv (80, 81, 8). T cncn bed n epermen perrmed ng eer nrml mce r mmndecen C7 mce expreng e cd mn (SC). SCI mceck e by genere rerrnged cell recepr nd mmngblngene nd eee re cmpleely devd ncnl nd B cellnl expemen ndced SCD mce wee cpble elbrngcved, HC cl pve mcrpge drng necn wLa mcyg, nd ey dplyed pl ence e necn repe ve been wn be blgry dependen nIFN. e bly SCD mce prdce FN w nevcllyebled ng nerng mnclnl nbdy pecc r mrne

FN. SD mce prereed n vv w nFN ed elbrecved, HC c II-pve mcrpge, nd ey ded wngnecn w be de ve La n ddn, IF cld bemmncemcly dened n cre pernn SCI plencyemled v w e ked La (HKL). remen SCplencye w n nd cmplemen bled er bly pdce FN wen exped HKL, eeby ndcng e FNprdcng cell w n NK ce (8 1 , 84).

Sbeqen de dened TNF nd mcpge w e ccr rered r e genern FN by NK cell (81-8). n vmn SCID pencye w HKL w nd eec prdcn bh NF nd IFN b w deren knec. ek evel NF were berved 18 r er mln nd wy peceded pdcn IFN wc peked ny er 48 r. Were e ddn nelng mnclnl nbdy NF prevened elrn IFN, cnrl nbde (ncldng nerng nbde pecc rmrne L) dd n. rever, necn nerlng nNF n

eer SCD r nml mce blcked e bly e nm prdceFN n vv nd mn n -La repne crpge rmnbdyreed, neced mce dd n w ncreed level HCcl , nd e mce led cler e bcer rm e pleen nd lver


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582 FAA & SCHIB

8 1 ) T lt t w tat gnatin fFN by timlatd SCDspln lls id t pdtin f NF

Cll dpltin xpimnts vald tat mapag w t llla f TNF ll mixing xpimnt ing p pp

latin f SCD NK ll divd by n it ppagatin f ll n L2swd ta FN pdtn d nly in t pn f mapags and bata in t pn f pd TNF and lblbatial pdt 82 83) n t latt a TNF aln wa nt intt ind FN pdtin fm NK ll. T NK ll atiatin tpd FN qi tw mpnnt TNF pdd pyilgiallypn xps f a mapag t a mibial patgn and a sndstiml tat an b a batial pdt akn tgt ts ltndat ta t FN pdd by NK ll pnt t t t linf dfn againt mbial patgn tat a ptbl t kill ing byatiatd mapag.

THE IFNy RECEPTOR AND MECHANISMS OFSGNAL TRANSDUCTON

FN xt it plitpi t n lls tg an intatn wit ap pt xpd at t ll fa On t bai f immnmial adiligand binding and mlla gnti analyss tappas t b nly a singl typ f FN pt tat is bitslyxpsd n all lls xpt t ytyt) 85 1 03 85) Evn platlt xp FN pt at a lvl f300 ptll 6) Cndingt ag nmb f platlt in t ilatin 3 1 0 m\) it i pibltat ti ll plays an imptant l in tanspting FN tg tilaty sytm t is ntwty tat wn pt xpin indnt tiss is analyd at it t mRNA ptin lvls tigt xpin i bd in ti nt gnally nidd t a

pimay immnlgi fntin 5; Lqtt J Caldn R DSib npblid slts). Spially kin nv and ynytialtpblasts f t planta xpss lvl f FN pt tat an 10-100 tims tat bsvd in spln n matpit llT pt bind lgand wit g anity Ka 1 0 _10 ) and ixpd n mt ll nly at mdt ll 2025000 itll)man and min FN pts dsplay stit sps piity in tiability t intat wt man and min FN

IFNy RECEPTOR SYNTHESIS AND RECYCLING

sing adiligand bnding and immnpipitatin tni t lifyl f man and min FN pt av bn patially lidatd


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FNy AND FNy CPT 8

(9100) Te ecep s syneed n e endplsmc eclm nd glycsyed mves fm e ER g e glg A les eegycsn nemedes w mlecl msses f 6 0 nd kDve been dened Onl ll lcyled ecep e expeed e

cell ce Cbyde nl ndce m n ll ecbydes e Nlnked Hweve Olnked glycsyln ecepsn sme ces s n been sngeny ed y me ecepsexpessed n e plm membne dply mlecl msses vybeween 80 nd 9 kD Ts mdes mlecl weg eegeney s esl f cellspecc deences n glycsyln llwng necnw lgnd e cell sfce e ncell dmn f e ecep spspled n sene nd enne esdes ( 1 0 1 1 02) Alg efncnl sgncnce s pspyln emns ncle e end exen f pspln celes peecly w e mgnde bilgi pn indd T ppyld pignd mplex s nenled enes n cded endsml cmpmen nd dssces ee N evenlly cs e lyssme wee s lmeldegded n mny cell c bbl e ncpled ecep ene lge ncelll pl f me ecep nd evenlly eccle bck e cell sce Te se f e ncelll ecep pl s genelly2 mes gee n e p f ecep expessed e cell sfce

(03-0) Te by f e N ecep ecyce n mcpgesemn cnvel Wees me ep ndce ecclng dendeed cc n ee pmy cled mnncle pgcyes (91 0 1 0) les ne e gp eped nenled ecepse degded n pmy mncyes (06)

Recepto' Stuctue

Recenly mn nd mne IN eceps ve been ped mgeney (89-92) nd ply cceed e cmplee ccenf e mn ecep ce ws mde pbl b e clnng fs cDNA s ccmpled by Age nd clleges n 1988 (10)Sbseenly sevel lbes clned nd expeed e mne mlge ( 1 08-1 1 2) Te genes f e mn nd mne eeps vebeen lcled cmme 6 ( 622) nd 1 0 epecvel ( 3 5e mn nd mne N ecep genes e ppxmely 0 kb ne ( 6 Ec cn f exn nd pn cvn gves se sngle 2 kb mRNA ncp Te eslng mn nd mne pens

e gned n ml mnne (Tble ge ) Te me pencnss f 42 nd 1 mn cds especvely nd ve pedcedmecl msses f 2 nd 48 kD B pens e symmecllened nd nge 2 mn cd nsmembne dmns Ec ps


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84 FARRAR & SCHRIBR

b oion o hn nd ine IFN eceo

N ecep

Ppey Huma ine

Pmy eencegnl pepde

e 4 451aalgy %

Din cexcelll nebne 23aaIncell

Penil Nlinked

ycoylion ie Pediced olecl wegh 63 499

lecl eigh lecle 90000 90000

eeene ceWole olecule 7 .6% %Extracelluar domain . % .%Incelll din % 4%

a 8 aino acid xtraclluar doain a conain l cyindu and potntal lnkd glycoylation Bad on oyntticabing xprint, al glycoyaion i appar to b occupid (98,99, 7, and lnkd oligoaccarid conribut approxialy 5 kDato t apparnt olcular wig of fuly atur proin Solublfor of t xaclular doain of t uan and uin F rcptorav bn producd itr in bacia o ukayoic cl 3 8 , 9 avaabily of t ragnt a d o dontraion a xraclluar doan ucn o accoun for g any ligand bndngand ta rcpo glycoylaion i no criical fo ligand binding activty rucurfunction analyi of ti doain a bn iniiad ooyicdigtion of rcpor oubl xtraclluar doain donratd tat ano rinal x ridu a no ruird fo lgand binding acvityHowvr, allt proolytic fagnt of vd olubrcpor capabl of xpng ful ligand binding actvty wa a 5 kDacoponn ncopaing ridu 7, wic i narly ni xtra

cllular doan (. Obviouly, or work i ndd bfor t ructural lnt of t rcpor ta ar involvd in ligand binding adnd

Bad on priary unc coparion, t F rcpor bar lil


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228aa

23aa

221aa

H

Glu

IN AND IN RECEPR 585

.-----,

,

,

l_J,

,

,.

Fue 4 e f the huma FN receptr he igad bidig chai i a gycprteicmped f 4 ami acid ad i ymmetricay rieted arud a ige ami acid

tramembae dmai he extraceuar ad itraceuar dmai are cmped f 22ad 22 ami acid repectivey he prtei ctai Nied igaccharide adpiby ied ugar me ce. he itraceuar dmai i rich i erie adthreie reidue me f which are phphryated up iteracti f th receptr withigad i itact ce w fuctiay imprtat regi i the itraceuar dmai haebee idetied haded area) he membae prxima regi reidue 260) i eed frbth receptrmediated iteraizati f igad ad iducti f bigic repe hecarbxy ermia regi reidue 43472) i eeded y fr bigc repe ductihe three critica ami acid withi the atter regi 40 4, ad H44) areidetied Fuctiay actie recepr reuire the preece f a ecd a yet udeed

accery mcue that mut be pecie matched t the FN receptr hw a thecmpet he right ide f the gure) he uggeti that thi cmpet i a membraepin i aed n in in humamurie chimeric receptr

Annu.R

ev.Immunol.1993.11:571-611.


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86 FAA & SCB

ideniy o any oter known proeins. pecically, i s neter a ebero e ype cytokine or eatopoietic receptor aily cracteriedby te positon o 4 conserved cyseine resdues and a ebrane proxialWXW oti nor te iunogobulin superaily (11. n act, e

seuence idniy beween e uan and urine FN receptors teselves is only 2% 0% ideniy between e extracelluar dains and% identity between e inracelular doains More rened structuraanalyses o e FN recepors exraceluar doain using predictive algoris ave ndicated at te uan and urne FN receptors belongo a new aily o cyokine recepors tered e ype cyokine receporaily wose ebers include e recepor or FN and issue actore ebers o is protein aily sare a siilarly organied 2 1 0 ainoacid binding doain wic contains conserved cyseine pairs a boano and carboxy ern e ype receptor aiy appears o beony distantly relaed sructuraly to te ype aiy ( 1 1

e inracellular doains o te uan and urine FN recepors are and resdues respectively Bo are paricularly ric in serine andtreonine residues ese two ano acids consiue approxiately 2%o all e residues wiin is doain. Moreover, e intracelular doainso te uan and urine proteins contan 6 and tyrosine residues,respectively ve o wic are conserved. is observation is paricularly

notewory because o e low overa seuence denity witn e uanand urine ntraceluar doans e receptors' intracelluar doanssow o signicnt seuence or strucural oologies to any oer knownreceptor polypepides Moreover, tey do not possess any identiablekinase pospaase, SH, or SH doain caraceristics. ereore, tepriary srucure analysis o e FN recepor as no provided insigtsino e ecanis o action o s proein

nctionINy Receptor Reqire Specie Specc

cceor Componentxpression o e uan and urine receptor cDNs across speciesboundares i.e n urine and uan cells respectvely conred tae cloned cDNs encoded proteins tat bound ligand in e appropratespeciesspecic anner and nernalied i wi kinetics a were indisinguisable ro naural recepors expressed on ooogous cels 71 1 However, e receptors expessed across species lines were unabe onduce a uciona response in e ranseced cells is resul suggesed

ta one or ore additonal species atced coponens were reuired toor a uncionally acive FN recepor t also suppored e conclusionsreaced in e seinal experiens o estka and colleagues wo in 987 used urine uan soaic cell ybrds o investigae e inial


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IFNy AND IFNy RCPOR 8

reureen o for a funconay actve huan FN recepor n urnece Fuon of urne and huan brobat wa known o generaetabe ce hybrd tha conaned the fu copeen of urne chroooe but ony a rando aortent of uan croooe

ybrd ta conaned huan chroooe 6, bound huan FN However, reponvene o the huan gand wa oberved ony n hybrda conaned bo uan croooe 6 and obgate reureent for wo (or ore dtnc peceaced ene produc ed to thehypote a funconay acve uan reeor were copoed of aeat two dtnct poypepde the FN recepor tef, reponbe forthe bndng of and, and a pece ached undened proen needed fordeveopen of functona repone n ce ( Durn the pa fewyear the vady of th hypothe ha been ncanty enhanced bye deonaon at expeon of e uan FN ecepto cDN nurne ce conann ony huan chroooe ead o foratonof a funcoay acve huan FN recepor capabe of nducng ot fno a FNdependen booc repone n te tranfece ce (-4.

Snce th acceory facor( ha no yet been dented, te knownabou ructure or funcon n huanurne cherc FN recepor prodced by nerchangn e exraceuar, ranebrane, and

nraceuar doan of he uan and urne proen e te of hepecepecc neracton between he receptor and e hun acceoryproen ha been ocaed o the receptor extraceuar dan (- reut uge bu doe no prove that he acceory oecue expreed a e paa ebrane n conrat ore known aboutthe croooa ocaton of the ene( encodng he huan receptoracceory coponent n urne ce contann uan choooe fragen, the acceory coponent a been ocaed to a one eabae area on han croooe n e regon. erengy,h reon ao conan e gene for he uan N recepor (8(ahoug the FN recepor known not o be the acceory coponentof te FN recepor Subeuen experen utng haeroueoatc ce hybrd have ndcated tha the gene( for e urne FNrecepor acceory coponen ocated on urne chroooe 6 9

Structure-Fuctio Relatioships withi the IFNy Receptor

n conrat conderaby ore nforaon avaabe concernng e

ructure ad funcon of he huan and urne FN receptor poypepde eeve e aby to reconue a uncona huan FNrecepor n rne broba ha conan huan chroooe habeen ued to ap he funconay porant reon of te uan FN


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588 &

recepors intracelllar domain (3, 30, 33 Fll lengh or trncated(ie a recepor lacking al b 3 amino acids of he inracear domainreceptors were stably expressed in mrine broblasts conaining a singlecopy of hman chromosome he cels expressing the fllength hman

recepor bond and inernaied hman IFN and responded o i bypreglaing expression of MHC cass I molecles In conras, cellsexpressing he trncaed hman receptor bond hman IFN b neitherinternalized i nor responded to it Sbseqen experimens tha sedreceptor deeion mtan idenied wo distinc regions of he intracelllardomain which were obigatorily reqired for recepor fnction (Figre 4he rs encompassed he 48 amino acids coses to he membrane (ermedregion I, resides 56303 and was reqired for both recepor mediaed

ligand internalizaion and degradaion and indcion of biologicalresponses he second consised of he 39 amino acids a he carboxyermins (ermed region IV, resides 4347 and was reqired exclsiveyfor biologic response indction (3 Alhogh region I has only beenparially characterized o date, a lecineisolecine seqence (resides 70-7 has been idenied within this region ha is involved in eecingrecepormediated igand internalizaion/degradaion ( 30. his seqencmaches a moif fond in he inracelllar domains of he and chainsof he cell recepor compex and in the cationdependen mannose-6

phosphate recepor which has been shown to direc the racing of heseproeins o ysosomes ( 3 , 3 he nding ha IFN recepor mtans,in which his seqence has been deleed or repaced by alanines, showdecreased degradaion of bond ligand sggess a similar role for hisseqence in directing he IFN receptorligand complex o a ate endosomal or lysosoma comparment

Region IV has been more exensively characeried (33 A pointmtaional analysis of this region (in which each reside was individaly

changed o alanine demonsraed tha only hree resides are fnctionallyimporan hese are yrosine at posiion 440, asparic acid a posiion44 , and histidine a posiion 444 Aleraion of any one of hese resideso alanine prodced a recepor which was nable to indce a variey ofIFNdependent biologica responses in mrine broblass ha conainedhman chromosome l hese incded indcion of IRF- (an IFNindcible ranscripion factor, MHC class I proein, and niric oxide. heparicar fncional imporance of yrosine440 was conrmed by woaddiiona observaions Firs, sbsittion of phenylalanine for yrosine

440 also relted in generation of a fncionaly inacive receptor hisresl sggess tha he hydroxyl grop present on the yrosine side chainplays an imporant role in he signaling process eiher by (i forming asrcraly criical intramoleclar hydrogen bond, (ii conribing to


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y A y ROR 589

intemolec poteinpotein intections, o (iii) seving s the tgeto potein tyosine kinse indced phosphoyltion econd, mttiono deetion o ny of the othe tyosine esides within the eceptosintcel domin did not blte ecepto ctivity Additionl sppot

o the ncionl impotnce o egion V is deived om micoinjectionexpeiments in which monoclonl ntibody specic o n ovelppingseqence to this egion (esides 388449) inhibited celll esponse toN (134) Micoinjection o ntibodies tht ected with the middlepotions o the intcelll domin (egions nd did not inhibitcelllesponsiveness hs tken togethe these stdies hve identiednctionlly citic egions within the intcell domin o the Necepto It is expected tht the exct oles o these two intcelll dominegions in the signling/inteniztion pocess wil soon be elcidted

Mechanisms of Signal Transducion

Recenty the impotnt obsevtion hs been mde tht N indcesdimeztion o its ecepto sing diolignd binding echniqes, scosedensity gdient ltcentigtion nd HLC ge lttion chomtogphy, the olbe hmn N ecepto extcelll domin(ECD) ws shown to om complex with ignd tht contined two moleso ECD n ony one mole o N homodime he stoichiomety o the

compex ws dependent on the eltive popotions o lignd nd eceptodded to the ection mixte At limiting inpts o N, 2 1(ECDIN) complex ws omed When lignd ws dded in vst ovebndnce it ws possible to demonstte 1: 1 complex, lthogh evennde these conditions the 1 complex seemed to be peeed On thebsis o this dt it is likey tht the eceptolignd complex omedphysiologicy t the cell sce s composed o two eceptos bond toone N homodime (3 1 3 1 ) ppot o this concept is deived omecent cosslinking stdies, which hve shown tht nde the ppopite

conditions 2 1 eceptoignd complex cn be immnopecipitted omhmn cells teted with physioogic levels o hmn N (D ennicD V Goeddel, pesonl commniction) A pevios epot sggestedtht N ws only cpbe o podcing 1 1 complex with its ecepto(35) Howeve, the ecombinnt soble ecepto sed in those stdiesws engineeed to contin cboxy teminl histidine esides nd it islikely tht the pesence o these mino cids inteeed with the genetiono the 1 complex (3 1 )

he physiologic eevnce o ligndindced ecepto dimeiztion islso stongly sppoted by the nding tht nctionlly inctive eceptosct s dominnt negtive mtnt when oveexpessed in omologoscells (32). hese stdies tilied mine L cells tht oveexpessed mtnt


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90 ARRAR & SRBR

mrine F receptors lacking either (i the entire intracelllar doman(i the carboxy terminal 39 amino acids (encompassing fnctional regionV, or (iii a receptor pont mtant n which alanine was sbstitted forthe mrine tyrosine resde (reside 40 corresponding to the fnctionally

important hman tyrosine40 Cell lines in whch nonfnctional receptorswere expressed at levels 100fold higher than the endogenos receptors nolonger responded to mrine FN when analyzed in a variey of assays(RF-1 indcton MHC class enhancement nitric oxide indction anddevelopment of antiviral activty n contrast comparable overexpressionof the wild type mrine receptor did not prodce a dominant negativeeect Inactvation of FN responsiveness was dependent on the ratio ofmtan endogenos receptors At 6: 1 ratios no inhibition was observedHowever a profond inhbition was seen at ratios of 2 1 and completeinactivation was achieved at a 1 00 1 ratio. his eect was not de simplyto competition for lgand by inactve receptor, becase the cells remainednresponsive to ligand even when exposed to FN concentratons 3 1 0

times higher than that normally reqred to indce a maximal response nwild type cells Overexpression of inactive receptor did not alter expressionof the endogenos receptor hs, ligand indced dimeriation of the FNreceptor, nd n particlar the formation of a dimeric form of the receptorsintracelllar domain may be a critical rst step in FN receptor mediated

signal transdctionSbseqet events in the sgnal transdction pathway are less clearlydened Whereas some reports indicate that the receptor ats throghsignal transdction pathways nvolvng protein kinases ( 1 3 10, receptorphosphorylation (101, 102, and/or ion xes (141, other investigatorshave sggested that the receptor is primarily responsible for transportinglgand nto the cell and propose that intracelllar FN somehow ndcesa celllar reponse ( 14244 Based on the strctrefnction expermentsdescrbed above, there is little dobt that receptormediated ligand nternaliation is ufce to ndce biologic responses in cells his conclson is baed on two observations First whereas hman FN receptorsexpressed in normal mrine cells eect lgand internalization and degradation wth knetics that are indstingshable from that of fnctionallyactive receptors, no biologic response s observed Second, mtant hmanreceptors lacking the carboxy terminal 9 amino acids region V, whenexpressed in mrine cells containng hman chromosome 21 are alsofnctonally inactive despite their abli ty to mediate ligand internalzaton

hs, the moleclar explanation for the reports indicating a eqirementfor ligand internalzation reman nclear It i s likely that ths ncertaintywill soon be resolved when the receptorrelated accessory component'sidentity and fncton are elcidated and when the mapping of the recep


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Fy AD Fy CPTO 9

tors intracellular domain regon (regon I) required for both internaliation and function is completed. Finally, the recent excting dentcation of key components of the IFN sgnalng pathway ( 47) andthe observation that the signal transduction pathways utilied by FN

and IFN overlap (8, 49) may provde addtonal nsghts that wllhelp dene he downstream signalling events and dentfy the functonalbranching ponts that characterie the pleotropic activities ofIFN.

IFN BIGY

Work performed n many laboratories during the past 2 years has unequivocally establshed that IFN is an extremely pleiotropic cytokine that hasunarguabe physiologic importance in regulaing mune and inam

matory processes o a large extent, ths research was made possibl bythe large scale avalability of highly puried recombinant human andmurne IFN and the generaon of neurang FNspecc monoclonalantibodies. Most recently, two new and exciting models of genetic IFNdecency n mce have been derved by ablating ether IFN receptor oIFN gene expression usng homologous recombnation and embryoncstem cell technologes ( 0, ) It is expected that these mice will providenw and excting nsghts into IFN bology

here is currently a vast amount o normaton avalabe concengIFNs bologc activtes It s impossible to cover this area n its entiretyin ths review article. herefore we have decided to focus on some of themaor biologc actvtes o ths cytokine and describe them n the contextof three systems which are of prime interest to immunologsts host defense,inammation, and autoimmunity.

IFN'S RE IN HST DEFENSE

y as a egulator of esponse nductionClearly one of the major physiologic roles of IFN is ts ability to regulateMHC class I and class II protein expression on a varety of immunologically important cell types hese include mononclear phagocytes,endothelal cells, and epthelial cells, to name a few (7, 62, 2 4).Interestingly, although FN acts to increase class I and cass II expressonon most cels it inhibits class II expression on B cells ( ) Whereas IFNand IFN can also upregulate class I expression on cells, they are not

nducers of MHC class II proteins. IFNs ability to perform these functions was rst appreciated n n vtro experiments in whch puried recombnan N was added to primary cells or cultured cell lnes and MHCpoen expreson monitored usng immunochemical technques (2)


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59 FAA & SCHB

Subsequenly, his observaion was conmed using wo ypes of in vivoappoaches. In he rs, IFN was ineced diecly ino he hos and MHCanigen expession monioed. hese expeimens showed ha FN couldupegulae MHC class I and class II poeins boh locally a he injecion

sie and sysemically In he second ype of expeimen, he hos wasinjeced wih IFNspecic, neualiing monoclonal anibodies and henexposed o an immunologic chaenge such as a parasiic infecion. Wheeashe issues and cells of conol animals displayed signican inducion ofMHC class II anigens on heir surface, cells fom aniFN reaedanimals did no he lae expeimen was paiculaly infomaivebecause i documened ha endogenously produced IFN plays an imporan physiologic role in egulaing MHC proein expression (8, 56More deailed analyses have shown ha IFN HC class Iexpession ( fold on cells ha consiuively expess class I and class II expession on cells ha are normally devoid of hese proeins ( 57A he molecular level, IFN has been shown o exer is aciviy byegulaing MHC gene anscipion MHC class and class genes conainacing elemens in hei pomoe egions ha bind o IFNinducedacing facors he molecular naure of hese elemens and facorsare curenly being elucidaed (58, 59 A he funcional evel, IFNdependen upregulaion of MHC gene expession is an imporan sep in

pomoing anigen pesenaion duing he inducive phase of immuneesponses ( 60-64 On mos cells, IFN is sucien o upegulae MHCmolecules However, is acion is ofen synegisically enhanced byaddiional endogenous simuli such as NF o exogenous agens such asbaceial o icrobial producs Imporanly, some cells such as pancreaicisles display an obligaory equiremen fo he combined acions of IFNand NF ( 65- 67.

he monocye/macrophage is a pime cellular age for FN undephysioogc odos Work o sra aoraors as dad haIFN is one of he maor cyokines esponsible for acivaing or oherwiseeguaing he dieeniaion and funcion of mononuclea phagocyes (58,68 IFN has been shown o eec he diereniaion of immauremyeloid pecursors ino maure monocyes I pomoes anigen preseningaciviy in macophages, no only hough he inducion of HC class IIexpression, bu also by inceasing levels of seveal inracellular enymesha may be impoan fo anigen processing ( 69, 70 In addiion, IFNaugmens expression of macophage cell suface proeins such as ICAM

ha enhance he funcional consequences of he ineracion beweenmacrophages and cells duing anigen presenaion ( 7 - 73IFN also ees s eecs on ohe cells of he immune sysem I

regulaes immunoglobulin isoype swiching on B cells (74 and ana


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IFNy AND IFNy RECEPOR 93

gonizes he ability of IL to induce MHC class I expression on mrineB cells ( hese responses result from the drect eect o F on theB cell. B cel responses are also inenced indirectly by IN's ability toreglate the development of specic sbses of CD4 + cells. IN has a

profond anti proliferative eect on the sbse of mrine CD4 celsbu no on (6, 6 he abiity to reguate CD4 ce activation/dierentiaion hereby esablishes IN as a key component indeermining the type of immne eecor fncion ha evenally developsduring he corse of an immune response (igure 5 he opposing eecsof IL and IF tereby serve to crossregate the development ospecic immune responses L inhibis FN producion by cells andN cells and hereby diverts the response o he humoral pole In conrastIN inhibits the expansion of like cells, hereby eliminaing a keycelllar source of IL 0. his event hen divers the response to the cellmedited imunit pole. he sggestion hs been mde tht N servesa posiive role in the generaion of CD8 cytolyic cels CL 76However, his hypohesis has not yet been stringenly demonsraed and, nfact mice wth genetic INunresponsiveness produce more CL aciviyduring a mixed leukocyte reacion than their norma conterparts 50 ] his reslt indicaes ha IF may acually exert an ani proliferaive

G

,

IL-10nhibts IFNy

Snthess

CE MDATEDMMNTY

I IFN sAntprolferative

,to TH 2

UMORALMMUNTY

I an IL croeglae te evelopment o pecic am o immneeeco ncn nb pocon b TH CD+ T ce an ce anerey ni evelopmen o cellmeiate immne repone At e ame tme IL acton pomoe eveopmen o moal immniy. In contra init teproieraion o TH + T cell teey initing proction o TH erve cytokineincling IL T reglaory action relt in te preerenial evelopment o cellmeiae immnity an e epreion o moral immnity. T intity o e ignal tatlea to e peomnance o IL ver I eec remain nene


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94 FAA & SCHEIBE

eect on he CD8 cell poplation as well as the CD4 2 cellpopaion

IFNy as a Reulator of Eector Mechanisms

hee can be ite dob hat IFN is he mao physiologic macophageacivaing facto (MAF and theefoe is the pimay cytokine esponsibefo indcing nonspecic cel mediaed mechanisms of host defense Wokfom sevea laboaoies has neqivocally established IFN's abi iy toactivae nonspecic cyocidal activiy in macophages owad a vaiey ofintacella and extacella paasies and neoplastic cells (4 80 77IFN (i indces he expession of as yet ndened stctes on macophages that ecognize tage cells and (ii pomotes the elaboaion ofmacophagedeived cyocidal componds sch as eactive oxygen ndeactive niogen-intemediates and NF (78 IFN also edces thesscepibiiy of macophage poplations to micobial infection (8 79he impoance of IFN in the cleaance of micobial pathogens hasbeen amply demonsaed sing animal models Mice peeaed wihnealizing monoconal anibodies o IFN lose hei capaciy o esoveinfecion initiated wih a sblehal dose of a vaiey of micobial pahogenssch as ea mncygene (80 8 6 Txplama gnd (80 oehmana maj ( 8 hese expeimens ths docment the capacity of

endogenosly podced IN to acivate maco phages nde physiologicin vivo conditionsCenty a geat deal of aenion is being focsed on IFN's abiiy o

indce niic oxide (NO podction in cells NO is a cella podctha appeas o play an impoant ole in eecting intacella kill ing ofmicobia pahogens in the mose Nitic oxide is geneated as a esl ofhe enzymatic convesion of Laginine to Lcilline ( 8 his eacionis caalyzed by a famiy of enzymes known as niic oide synhase (NOSA leas 3 foms of he enzyme have been idenied ( 83 wo ae ex

pessed consitively in a issespecic manne (endoheim and nevostisse and podce ow levels of NO ha fnction to eec cellcel commnicaion In contas he hid is an indcible fom of the enzyme whoseexpession is ontoed by two simli: IFN and a second signal hesignals that igge NO podction in IFN pimed cels ae a divesegop of endogenos and exogenos sbstances sch as NF IL l LSand whole baceia ( 84 8 he aay of componens hat igge NOpodction in cells vaies depending pon he nate ofhe NOS podcing

cell Fo exampe in maco phages NOS is indced by IFN and NF btno IL l while in ceain boblasts o panceaic isles NOS is indcedby IFN and eihe NF o IL-l ( 8 . C F Sheehan R D Scheibe

Annu.

Rev.Immunol.1993.11:571-611


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IFN AND !Ny POR 9

unpublshed observations) he inducible macrophage NOS has recentybeen cloned and chaacezed ( 8 88) Wheher he nducble NO synthase expressed in other cell types is denical to the macrophage enymeneeds to be estabished

IFNdependent formation of nitric oxide appears o be a maor mechanism in the mouse for the macrophagemediaed klling of intracellularpathogens Much of his information has been geaned from he study ofmurine modes of nfection wth Leshmana or Lstera. Macrophagesexposed in vro to IFN and infeced wih either Leshmana amasigotesor Lstea develop the capacty to kill the intracellular pathogens Kiings compleely inhibited when the macro phages are treaed with competiiveinhibitors o NOS such as the Larginine analogs NmonomehylLarginine (LNMMA) (8) or amnoguanidne (89) In vivo, the mporanoe o Fdepedet dcto of NO me modes of mcoammuny has been ndcaed by a leas hee ypes o epemens Fsmce undergong acive infection produce NO as detected by the presencen the urne of the stable (NO) oidaion produc nrte (N). Nproducton was blocked when the mice were reated wih neuraliingmonoclona antibodies specc fo either IFN or NF (8) Second,killing of ve Leshmana in vivo at a local sie (foopad) was ignicanlydecreased when the animals were treated wth the NOS inhibior NMMA

(90). hrd and perhaps most signicant is the recent observation hatmice treated with aminoguanidine succumb o infection with a sublehaldose of Lsea monocytogenes, much like mice treated wth aniIFN(K Beckerman H Rogers C rip J Corbett R Schreber M McDanielE nanue manuscript in preparation) Inerestingly human mononucear phagocytes have not been shown o produce nitric oxde or NOShus far (ahough human slets and hepaocytes can deed produce NO)Whereas ths aer observation may indicate tha speces specic dier

ences exst in Ndependent macrophage mediaed cytocidal responses,the possibiity must also be considered that the human mononuclearaoce eqes a addtoa signal o dce NOS

In addiin to enhancig nonspecc cell mediaed cytocidal activesIFN also enhances the abiliy of the macrophage to particpae n oherimmne response eector funcions I ncreases epresson of hgh aniyFc recepors on monocytesmacrophages (FR and thereby enhancesthe capacty of these cels to paricipate in antibody dependen cellularcytooxcty (ADCC) reacons (9) IFN also enhances the bosynhess

of a varey of complemen proeins (such as C, C4 and Facor B)by macrophages and broblasts (192) and regulaes the epresson ofcompemen receptors on he mononuclear phagocyte pasma membrane


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96 ARRAR & SRR

erey roog ora y rog eacee o coee acvy

Ny N TH NAMMATORY RSPONS

A ssaa ao o daa s ow avaae a sppors e cocepa cokes a a aor roe roo aaor resosesF aso parcpaes s process arge rog s ay o eaceTF prodco ad/or acv Te ocs o s seco s ereore ogg e pora syergsc aco o F ad TF aao

N Reglation of TN Prouction

s ow we esased a LPS saed acropages prodcecreased aos o T F we cocoay reaed w F ( 93196) A ew eary sdes dcaed a F cod drecy dce TFprodco acropages However s res was o ssaaed oer aoraores ad s ke a e dco was a res ocreased sesvy o Freaed ces o ow eves o LPS prese e ed F ca case e pregao o LPSdced TFprodco a vare o dere re acropage popaos

cdg resde ad eced peroea edae acropages ad oearrow derved acropages grow vro Ts e ay o F oeace LPSdced F prodco s o srogy depede o eacvao sae of e acropage. Togycoaeeced acroagescocoa saed w a xre o LPS ad F dspaed 68es ger seadysae eves o TF specc RA a ces reaedw LPS aoe. Maxa eves o T F RA were aceved orsaer exposre o eer LPS aoe or o e LPS/F xre (93 9F aso eaced e ay o LPS o dce e TF roe (aseasred 6 r aer sao). Eacee o TF prodco wasos evde ce s prereaed or 4 r w F was s deecaeeve we F was added 6 r aer LPS sao (93 F caaso correc e geec deec acropages derved ro e LPSresosve C3H/He ose. C3H/He acroages do o prodceTF we saed ee vvo or vro w oderae coceraos ( g/) o LPS However ogycoaeeced acroages o ese ce reaed w ysoogc coceraos o pred

recoa re F rodce o TF RA ad proe wesaed w LPS a g/ (193).Severa sdes dcae a e eacee o LSdced TF

rodco y F s a res a eas par o creased rascrpo


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IFy AD IFy REEPTR 9

o he TF gene ( 9-19 , 1 9, 1 9) However, he sggesion has asobeen made ha in his sysem, F may aso increase F mRAsabiiy n par his aer hypohess is based on he demonsraion ha F mRA conains an ocomerc seqence (UUAUUUAU) wihin is

3 nransaed region ha i s a poin o aack or a seecive nceoycaciviy capabe o hydroying mRA Simiar seqences have aso beenond in he n ransaed regions o oher shorived cyokine mRAsSUCR as hoe ha encode L- and GMCSF ndependen sdies haveshown ha he haie o F mRA s ncreased in cycoheximidereaed ces simaed wih LPS hereore i seems key ha F mayexer some o s enhancng eecs on F prodcion by inhibiing hegeneraion o his shorived represso acivy ( 99)

F has aso been shown o enhance expression o F recepors ona variey o dieren ce ypes (000) reamen o ces wh Fdoes no aer heir igand binding aniy b ncreases recepo expresson- od. oh ypes o F recepors (p and p) can be ncreasedby F Enhanced recepor expression appears o be de o increasedproen synhess and no o ransocaion o recepors rom an inracearpoo snce Fs eecs can be bocked by reamen o he ces whacinomyci D. However, he bioogc signicance o his eec remainso be esabished becase no correaon has ye been od beween

he eve o F recepor expresson and he magnde he cearresponse indced (00, 0 , 03)

Cellular ecruitment

ring an inammaory response, ces eave he circaion and migraeo he poin o necon Drng his process hey ms rs bind o andhen exravasae hrogh he vascar endoheim F an F canpromoe he expresson o overappng ses o cesrace moeces ha

pay an imporan roe in hs process ( 1 1) Sdies sing cred hmanmbica vein endoheia ces (HVEC) demonsraed ha in viro reamen wih F indces a sgncan b moderae increase in CM-(od) and MHC cass moeces ( od) b no indcon o ELAM-1 ( 1 1 , 04) n he same seing, T provoked a dramaic enhancemenoCAM expresson (40od) as we as moderae increases in ELAMI and MHC cass proteins However when HUVEC were cred inhe presence o boh F and F, he expression o a hree moeceswas enhanced in a synergisic manner wh CAM- and cass showng

0 and 4od ncreases, respecivey n addiion, he combinaion oFNy and TNFa indced ELAM expression on a signicany higherpercenage o ces han F aone n he presence o boh cyokinesELM aso dispayed a onger haie a he ce srace his aer


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9 ARRAR & SHREIBER

eet may est in a pngatin f te endoteia es abiity t eitiating ympytes (04 s te abiity f FN and NF tenane epession of e sfae adesion moees ay seve to epandand ampify te ovea inammatoy espnse

e peative abiity f FN and NF t mdate e migationwas onmed in in viv epeiments (0 Skin biopsies taken fmbabons teated intataneosy wit bot FN and TF wee fondto ontain twie te nmbes of monoytes ompaed to animas inetedwit eite ytkine ane Epessin f ELAM- CAM and MHCass mees was as synegistiay enaned in animas teated witbt ytkines

Shock

TNF as ong been knwn t mediate many f te ti eets f LPS(06-0 and is a key mediat in te Swatman eatin (a mde ofPSmediated tisse damage (09 0 n te assia Swatmaneation anmas ae initiay teated wit a oa sensitizing dose of LPS( g foowed ate wit a povoative intavenos dose of LPS(00 g e pysiogi espnses evked by tis pt mimi tseseen iniay in septi sok and disseminated intavasa agatinand inde emoagi neosis bin and pateet mediaed vasa

osin and amation ofnetopis at te oa site (06 0 Using te Swatman eation as a mode to investigate te meanism(sinvved in LPSinded disease sevea investigats ave swn tatFN pays a ia e in te pgessin of tis inammaty espnse(09 - Teatment of animas wit FN pio to sensitiation witLPS eads t enaned podtion ofTF and ineased motaity ( 3 Cnvesey teatment of animas wit netaiing FNspeimnna antibdies pi to inetin of te sensitiing dse f LPS

ptets tem fm te patogi eets f te pvative dse ( tis possibe tat te FN poded in tis eation is deived fom NKes in a manne esembing tat desibed abve fo te SCD mosee sensiting dse fLPS may stimate esting maopage t pdeF TNF and LPS ten may stimate NK es t pde and seeteFN NK edeived FN ten sd pime te mapages in eviinity to pode opios amonts of TF (and ote inammatymediatos s as L- and L- wen eposed to te povoative dosef LPS One poded te age amonts f TNF ten wd inde a

asade f eatins tat ave immnpatogi nseqenes Ts intis mde FN seves a ia intemediay e in ativatin f eetmapage popations A simia e f F was noted sing a mdeof endotoin sok ( Mie peteated wit eombinant mine FN


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Iy A y OR 599

18 r prior to intravenous injection wit an LD dose of LS sowedsignicantly increased mortality (92% dead at 72 ours). Conversely, micetreated wit neutraliing IFNspecic antibodies prior to administrationof an LD dose of LS were protected (218) from LS induced etal

sock. us, LSinduced FN appears to be a key mediator in tedevelopment of te immunopatoogic consequences of inammatoryresponses.

IFN IN TIMMNITY

Altoug IN appears to play a participatoy role in te developmentof some autoimmune processes, dierent experimenta models ave yieldedconicting interpretations as to its immunopatoogic versus protective

roles One model in wic FN as been impicated as a ausative agentis te development of autoimmune nepritis in te (NZB x NZW)Fmouse, a syndrome wic produces a patoogy similar to ta seen in teuman disease, systemic lupus erytematosis. Administration of exogenous IFN to (NZB NZW)F mice acceerated te prgression of spontaneous glomerulonepritis (50% surviva = 9.5 monts for control animals and 7.5 monts for FN treated mice) (219-221) Conversely,animas treated wit FNspecic monoconal antibodies displayed sig

nicant remission and increased survival (220). Additional upport forIFN's roe in producing tissue specc damage tat leads to autoimmuneresponses as been obtained from experiments utiliing transgenic miceexpressing te FN gene under te control of te rat insulin promoter( ese mice develop a severe insulitis and become ypogycemic andtereby deveop a syndrome tat appears very muc lie insuin dependentdiabetes meitus wic is commonly tougt to be an autoimmune disease.

n contrast, IFN plays a protective role in certain murine modes of

experimenta autoimmune encepalomyelitis (EAE). is demyelinatingdisease can be generated eiter by active immuniation wit myein basicprotein (MB) in adjuvant or by te adoptive transfer of encepaogenicMBspecic CD4 cel cones (223227) Immunization of C57BL/6or SJL/J mie wit MB results in moderate or leta forms of te disease,respectively 22). Treatment of C57BL/6 (moderate disease) mice witantiIFN exacerbates disease and eads to increased mortalityConversely, treatment of SJL/J mice (wic normally exibit 1 00% mor

tality) wit IFN led to enanced survival. us, using te acive immniation protocol, FN appears to downregulate te developmnt of EAE.is protective role is not observed wen EE is induced using te passive ce tranfer protoco Moreover, administration of FN to uman


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00 FAA & SB

ubjec wit acte utple cleroi te naurl uan deae aeeble uine EAE) lead to an exacebaton of te dieae 8)oeter tee reult deontrae a FN can pla dieren role ine deelopen of ariou autoiune repone and a ac trou

a ariet of dierent ecani Furer expeientation i requiredo deerine e olecular ecan) reponble for te eeinlconadico ole of FN in auoiune dieae

CONCLDING RMARKS

In cae we ae eewed oe of e ecen deeloent atae incantl added to our underandin of e biocet andbioo of FN. o a lae exen i poe wa ade poibe b e

ecnoocal adance at ae occurred wiin recent ear i te eldof olecular eneic, proein ceir, and cell biolo We now knowa rea deal abou e trucue of e FN olecue and it recepto, andwe ae beun o idenif wc of te funciona aciie of e proteinare piolocal reeant Neeree te olecular ecan aundeie FN' leooic acti eain undened, and we il ae noe found a ean o full deelop te oein' erapeuic otenial. ti ie tat tee ubec wi be e focu of fuue FN eeac

KWLGMS

e auto ae aeful o Micel Aue, aren Becean, anaDalton, Gianni Gaoa, Daid Goeddel, Diane ennica Katleen Seean, and i Unanue for arn unpubied daa and to Dr arleBu and Mcael aron for uppn e teeo pcure of e uanFN olecule. We alo wi o acknowede Dr. Katleen Seean forer adce on ue concernn FN biolo. n addiion, we ank

Maian Floea fo ecetaial aitance e wo decribed fo ourlaborator wa upported b NH ant A43059 and A24854 and aeneou if fro Genenec, nc.

Lteatue Cted

Wheec E. F 9 tererieiruhiit duced i huma eu-cyte y phyhemaggutii -ene 49

Peta age J A. Z K c,amue E. 9 terer ad

ther act Annu. Rev. Biohem.

tewart W E 99 The ntefensew r prgeVerag

4 ec K Briu J Fujawa A.

Fujawa .., aye J R chtadt . Kacic Pae ,chambc A chmd J drK Wachi , Nagata Weima 9 tructurareatihi huma terer

apha gee ad peudgee J. Mole.Bio

Dead W F Waema Z Rhwdhy V 99 euece adrucura hmge amg type I


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Sci USA 7: 70-3 Zoon K. c Mier D . Bez J zu

Nedden D Entene C NuyenN Y Hu, R Q 992 Puicaion andcaacerzaon of mutipe component of human Iympobatoidnerfeon apa J Bo Chem 2652 - 6

8 Zbertein, A. Ruier, R, Kor H Reve M 988. Sructue andexpeon of cDNA and gene fouman nterferon-/, a dtnc peces

nducibe by gowttmuatory cytokine EMBO J 5 2529-39 Van Snc J 1990 neeun An

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982 preion of human immunentefero cDNA in E col and moneyce Natre 295 5038

2 Gay P W Goedde D V 98Stucure of the human mmune interferon gene. Natre 298 85963

3 Gay P W, Goedde D V 983Conn and expreon of muineimmune intefeon cDNA Pr NalAcad c UA 80 842-46

4 Pace L. ue S W LeBanc PA Murao D M. 985 Comparative eect of vaiou cae of mouenteeon on macopage acaionfo tumo ce iing mmunol 3498

5 De Mayer E 84 Th inerferoytem and the mmune ytem nnterferons and the mmne ystem,ed Vice . De Maeyer pp 6Amtedam evie

6 Nayor S L, Saaguc A. Y ShowT. 8. Law M. L, Goedde D V.Gay P W 983 Human immuneinterferon gene i ocated on cho

moome 2 Exp ed 5 0202. Nayo S. L Gay, P W, Laey PA. 984 Mouse mmune ntefeon(FN) gene i on human cromoome 0. omat Cell Mol Genet 0 5334

Nl ND Nl PO 601

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9 Chrivia, C Wedrychowic, T,Young H A Hardy, K J. 990 A

me o han yon uaonbaed on tanfecon of amma ntefeon ene fament decy no oated peiphea bood T ympocyeJ Exp Me 2 66 -6

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Pottancptona cono ofuman amma nefeon ene expeion n aneced moe obat Mol Cell Bo 6 223-6

22. Young H A Day F aa WL. 986. Epreon of tranfeceduman ineferon-amma DNA: evidence o cepecc reguaton JImmunol 36 4003

23 Derync R Leung D. W. Gra PW Goedde, D V 9 82 Human ntefeon amma encoded by a geca of mRNA Nuc Acd e. 0

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Rodruez, H 984 Naura umanntefeon-gamma Compete aminoacd equence and detemnaon ofie of ycoyaon Bo Cem259 690-9

25. Scahi, S Devo, R. Van deHeyden e, W 83 peionand chaacteaon of te poduct ofa uman mmune ntefeon DNAgene n Chinee hamte ovary ceProc Natl A cad c A 80 4654-58

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2 Cang T W Mcnney S Lu ung P. Vice Le, 984. Ueof monocona anibodie a eniveand pecc pobe fo bioocayactive human gamma-nteferon ProcNatl A cad c UA 8 29-22

28 Aaawa, T Hu, Y R Pae C G La P H 986 Roe of poycaionc Ctrmia portio in h strucur anacvity of ecombinan uman nefeon-gamma Bo Chem 26 83439

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Seienain eqbri easre-ens rebinan DNA eriveman inerern gamma Bochestr 26 5422-27

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rembinan an an mrineimmne ineerns by means ei-menin eilibrim. J. tfoRes. 7 3 320

3 Greenln A c, Wenner, C. A.Sreiber, . D 2 Analysis FN reepr bning FN. Jterfeo Res. (Absr) 2 S03

3 a Fnlais M la M LsigA Gara G 2 Siimery inerain beween nerern an sreepr Eur. J. Boche. 0

3 Dige A. S. Farrar M ber. D. 3 Inibiin ellar resn-sveness IFN ine by verex-pressin naive rms e IF Nreepr. Bo Che. 268 In prss

33 Yngner J S Salvn, S B 73 Pr-in an reries migrainnibiy a an ineren in eiran e wi eaye yper-sensiiviy. uol 94-22

34 Hs, Y. Araawa T. Srral sies n a nlng anreing rembinan man ner-

ern gama. Bochestr 24 99-63

35 Araawa T. Hs, Y , YpansD. A 7 Ai ning an seassiain rembnan scherichacolerive an inerern gama.Bochestry 26 42832

36. Mlerri M G Weel, pHepenene e reversibe an rrevebe ermal enaran gaa inererns Bochestr 28 666

3 Pae J L. ssell S W Sreber

. D. Aman A Kaz D. H. 3Marage aivain rimingaiviy a Te ybria saribabe inererngaaProc. Natl. A cad Sc USA 80 382-86

3 ele c, Yi Y K. AnesnP Vie J. 983. Ees gy-siase reaen n e pysi-eal preries an bilgialaiviy man inererngama J.Bo Che 28 803

39 Keler, H c Le, J, bin, B Y YiY K., Nagler C. Vile J 4 Tree

melar weig rs naraan iererngamma reveale byimmnreiiain wi mnlnalaniby. J Bo. Che. 29 430-4

40 enran irner H Paraineis rembnanrine inererngaa in ie J.Iterfero 5730

4 Canell K Selleens PyaaL. Hirvnen S Van er Meie PH De es A 986. Parmainei

ies wi an an a inererns-gamma in ieren speies J Iterfo R 6 6775

42 . Jnsn H M Langr M PLaara B Can T. S . Sann,G. J. 982. Neralian naivean gama inerrn (HIFNgamma) by anibies a syneieie ene by e 5 en IFN gama DNA. J.Iuol. 29 2379

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M Tes B A, Dnn B M.ssell S W. Jnsn, H. M 6Ee an nina seiy mnlnal anibies se iner-erngamma e synei pepieara. J. Iuo. 36 33242

44 Magazine H Carer J M ssellJ. K Trres, B A Dnn B M . Jn-sn H. M. 988 Use syne ep-es ieniy an Nermina epien mse gamma inerern a maybe invlve in nin roc. Natl.

Acad. Sc. USA 8 23-44. Jarpe M A, Jnsn H M 0Tlgy reepr bnng mains mse IFNgamma J. Iuol4 33049

46 Jare M A Jnsn H M 990.Srre an epipe in an mninan regn e inerern-gamma mele a is invlve ineer nean R0 243-2

47 Hgree, . H MPie P Beis, JB, Enerline J. C. Dyer D. Webb, D

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49 Zavny P J Per M E., CiangT , Narla S. K Leibwi P. J. Alerans e ain er-ins mrine inererngammaeressin an bilgil iviy JIterfero Res 8 483-94

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50 Lenkk, . O. , adeon, , Luuee,M H., Schreber, R . 98 Reducedreceptor bndng by a human nterfeongamma fragmen ackng car-boxytermna amno acd. Iuol 9: 6066

5 Seeg, G. , Wjdene, J , Nagabhuhan, T L, Troa, . . 1988 Ev-dence for a poypeptde egment a thecarboxy termnu of recombnanthuman gamma nterferon nvoved nexpreon of boogca actvy Bocery 988

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T. L, Trotta, ., ugg, . E. 99.Threedmenona trucure o f recom-bnant human nerfeongamma. Scece 5: 980

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99. H, and N NM R backboneagnment and econdary ructure ohuman nereron Boetr 8890

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IFy A Iy RECPOR 60feron gamma: a ymphokne or aeaon ypoe

58. Scheber R , eada, A 985.Moecuar characeraton o nter-feron gamma a a macrophage actvatg actor ypoe 8 8

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ung recombnant IL2 and recom-bnant Ngamma. J. Iuol 45

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nducon n human perphera boodce by exogenou and endogenouyproduced ntereukn . J Iuol 5 : 8556

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Chan, S Trncher G erssa 99 . Conng of cDNA for naraker ce matory facor, a heero-dmerc cyokne wth mpe oogceecs on T and natra ker ces mmuo 46 307480

73 Sern A S odask, J , mes J D. , an, Y , Qnn, M WotzkyA G., ame, . Stremo D LTr, T Chzzone, R Gatey M 990 Prcaton o homogenetyand para characteraton of cyooc ymphocyte matraton factor

from hman Bymphoasod ceso Na ad Sc S 7: 6027 Chan S oayash M., Santo,

D., Perssa, B, Trncher, G 992Mechansms of Ngamma ndcony natra ker cel stmatory facor(NSIL2) Roe of ranscrptonand mRA say n the synergstcnteraco eween NS and IL2 mmu 48 9298

75 orentn D ond M W Mos-mann T R 989 Two types of moseT heper ce IV: TH2 cones secrete a

facor hat nhts cytokne pro-dcon y TH cones. E d 70 208 95

76. Moore, W Vera P., orentnoD Tronstne M L. han T.Mosmann T. R 990 Homoogy ofcyokne synthess nhtory factor(IL) to the pstenarr vrs geneBR! S 2 2303

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