~

CL.t

0'-'.c~,

4

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364 SURGERY, Gynecology & Obstetrics. April 19~

endothelial cells and natural killer cells also syn-thesize this protein (6). Expression of cachec-tin/TNF is tightly controlled, both at transcriptionaland translational levels (17). Whereas unstimu-lated monoC}'tes express low levels of cachectin/TNFmessenger Rl'\TA (mRNA), stimulation inducesboth increased transcription and increased trans-lation of the protein (17), leading to the releaseof mature protein within minutes.

Synthesis of cachectin/TNF is elicited by nu-merous infectious or inflarnmatory stimuli, includingbacteria and their cell wall-<lerived lipopolysaccha-ride (LPS) (17). Bacterial exotoxins, protozoans,fungi and vira! particles also increase transcrip-tion and translation of cachectin(INF (18, 19). Oncesecreted, however, fue half-life of circulating ca-chectin/TNF is brief, approximately 14 to 18minutes in humans (20). In animals, injectedradiolabeled cachectin/TNF is degraded in manyorgan systems, i~cluding the liver, skin, gastro-intestinal tract and kidney (4).

Mter bacterial infusions, circulating levels ofcachectin/TNF in rats, rabbits (21) and baboons(22) increase ,\'Íthin minutes, reach a monophasicpeak within 90 to 120 minutes and return tolevels below detectable limits in approximatelyfour hours. Bolus LPS infusions in animals and hu-mans al so induce a similar monophasic pattern,with circulating levels peaking approximately 1.5hours after such infusions (22). The sources ofcirculating cachectin/TNF appear to includeperipheral blood monocytes and splanchnic tis-sues (23). This brief monophasic appearance hasimportant implications. First, effective endogenousmechanisms exist to protect against continuedproduction of these potentially harmful agents'Second, fue brief appearance of cachectin/TNFis nevertheless sufficient to induce the releaseof a cascade of secondary cytokines and humoralfactors that mar lead to both systemic and tissueresponses. Third, even this brief exposure of ef-rector tissues to cachectin/TNF mar be sufficientto produce biologic sequelae directly.

Cachectin/TNF is detected in the serum ofpatients experiencing various diseases, includingparasitic (24) and bacterial infections (25),tumor-bearing disease (26), thermal injury (27),renal allograft rejection (28) and fulminanthepatic failure (29). Circulating amounts greaterthan 100 picograms per milliliter during menin-gococcal infection is associated ~'Íth increased mor-tality (25). Although circulating amounts ofcachectin/Tl"F and other cytokines mar be usefulas markers of injury and even of severity of injury,interpretation of absolute circulating amounts

/O .VolU1ne 170

must be performed "lith caution. It is clear thatmany cytokines are bioactive at levels well belo,'lthe range of detectability by current immunoas-says. It has been demonstrated that plasma ,'lithle\'els of cachectin;1NF below fue detectability of rur-rent ellZ}'l11e-fu1ked irnmunosorbent assa)'S (ELISA)mar, nonetheless, have effects on skeletal musclespecifically attributable to this cytokine (30). Thephasic nature of the release of cytokines duringinjury further renders the interpretation of iso-lated blood levels difficult. Results of longitudinalstudies ,'lith repeated blood sampling (27, 31)mar yield a greater correlation benveen circulat-ing amounts of these proteins and disease.

Cachectin/TNF is an endogenous p}Togen (32)"ith immunostimulatory actions that are impor-tant in combating invading organisms. This pro-tein elicits the release of neutrophils from thebaile marro,'l. In addition, cachectin/TNF ini-tiates neutrophil margination, transendothelialpassage (33) and activation (34), including de-granulation, production of superoxides and re-lease oflysozymes (35). The activation ofneutrophilsenhances antibody-dependent cellular cytotox-icity and neutrophil-mediated inhibition of fun-gal growth (36). Cachectin/TNF also pro motesdiH'erentiation of myelogenous cells to monocytesand macrophages (37) and induces activation ofmacrophages (38). Activation of macrophagesparticipates in the inhibition of intracellularreplication of viral and parasitic organisms (39),and increases cytotoxicity against virus-infectedcells (19). Thus, cachectin/TNF appears to bean important endogenous antiviral and antibac-terial agent.

In addition to modulating immune function,cachectin/TNF is a potent effector of metabolicfunctions in somatic tissue. It exerts direct effectson carbohydrate metabolism in muscle cells,which is characterized by increased cellular mem-brane transport of glucose, depletion of cellulargIycogen and increased ceIlular effiux of Iactate(40). Thus, cachectin/TNF mar represent an im-portant early signaI for the induction of anaerobicgIycolysis within somatic tissues.

Cachectin/TNF aIso influences the metabo.lismof proteins in the body. In vivo, cachectin/T~Fincreases degradation of protein in skeletaI mus-cle (41). Chronic administration of cachectin/TNF(42, 43) in animaIs causes protein wasting, aI-though most Iikely through secondary hor-mone-mediated or cytokine-mediated events. Inhumans, cachectin/TNF acutely induces a netrelease of amino acids from an isolated extrem i ty

(44).

~~~

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~

CUJar

FongIn contrast to the net catabolic effects of this

cytokine on peripheral tissues, cachectin/TNF isanabolic for hepatocytes. In hepatocyte celllines,cachectin/TNF enhances the expression of cer-tain acute phase proteins through changes intranscription rates (45). In ,ivo, exogenously ad-ministered cachectin/TNF algo enhances preser-vation of hepatic mass and increases circulatingamounts of acute phase proteins (46) and actssynergistically with glucagon in mediating in-creases in hepatic uptake of amino acids (47).Thus, this cytokine mar be important not onlyin the wasting of lean tissue that is associated""ith disease, but mar algO be instrumental inthe redistribution of proteins from fue peripheryto the liver during injury (42).

Cachectin/TNF elicits changes in metabolismof fat, similar to the changes observed in infec-tion. In vitro, cachectin/TNF has been shownto produce a net loss of triglycerides directlyfroliIl fue adipocytes by decreasing clearance ofextracellular lipids (4, 48), inhibiting the synthesisof fatty acids (49, 50) and increasing cellularlipolysis. Furthermore, this C)'tokine stimulates in-creased hepatic lipogenesis in vivo (51). Thesealterations in lipid metabolism mar contributeto fue hypertriglyceridemia and fue exaggeratedloss, of body fat seen in infection and othercatabolic processes (52).

Cáchectin/TNF has an important role in fueformation and remodeling of ,,-'ounds. This cyto-kine increases procoagulant activity on the endo-thelial surface and increases vascular permeability(53). ~dditl°nal!y, cach~5tin/T~F is a {lro~th faC::-

: nence, production of this protein after sur-gira} injury or bacterial infections potentiallybenefits immune resistance to invading organismsin the host. In addition, this C)'tokine is importantfor the mobilization of peripheral stores of lipidsand nitrogen as fuels and substrates for gluco-neogenesis and for the synthesis of proteins re-sponsible for host defense, such as acute phaseproteins and coagulation factors. Cachectin/TNFal so facilitates the sequestration of bacteria,localization of injury, as well as wound remodel-ing.

By contrast, an exaggerated or chronic secre-tion of cachectin/TNF mar underlie the path-ogenesis of two particular clinical situations thatare detrimental to the clinical outcome of theI host: cachexia and shock. Cachectin/TNF is

'; proposed to be a mediator of the cachexia seen"in chronic diseases, such as malignant and para-

et al... BIOLOGIC CHARACfERISnCS OF CYTOKINES 365

si tic diseases and tuberculosis. Not only are levelsof circulating cachectin/TNF higher in patientsafflicted with such diseases, but chronic ad-ministration of sublethal doses of this proteinin experimental models also reproduces manyof th~ physiologic findings observed in thechronic wasting associated with clinical disease.'In rodents, prolonged administration of cachec-tin/TNF decreases intake of food (42, 43, 46),increases loss of nitrogen (41) and induces de ple-tion of body lipids (43) and loss of weight.Tumors secreting recombinant human cachec-tin/TNF implanted into nude mice also producea similar syndrome of severe weight loss andcachexia (56), which adversely influences survival.Additionally, chronic administration of cachec-tin/TNF reduces the number of erythrocytes( 43), ,vhich is reminiscent of the anemia ofchronic disease. This anemia is caused by boththe decreased synthesis of erythrocytes and thedecreased life span of fue erythrocyte (57).

The acute, exaggerated secretion of cachec-tin/TNF is thought to be pathogenic in the car-diovascular collapse, state of shock and deathassociated with severe infection or endotoxemia.Administration of high doses of cachectin/TNFin animals can precipitate a syndrome similarto that seen in human septic shock. Acute in-fusion of high doses of cachectin/TNF in ratsproduces hypotension, lactic acidosis and death.Pathologic findings similar to those seen duringseptic shock, including adrenal necrosis, pul-monary congestion, cecal necrosis and ischemiaof other regions of the intestine, are also seen(58). Similarly, acute high dose infusions ofcachectin/TNF in canines also produce cardiovas-cular collapse with progressive hypotension,decreasing cardiac output and death (59). Thisresponse is associated with a rise in circulatingcounterregulatory hormones, release of lactatefrom the isolated lower extremity and a depres-sion of the resting membrane potential of skeletalmuscle. Additionally, extravascular sequestrationof fluids occurs, as evidenced by increased re-quirements for fluids after the infusion of cachec-tin/TNF.

The most convincing data on the role of cachec-tin/TNF in the pathogenesis of endotoxic shockcomes from fue results of studies in which ablockade of cachectin/TNF was used during bac-terial and LPS infusions. Prophylactic administra-tion of a rabbit antiserum to cachectin/TNFconferred survival benefit upon mice (60) andrabbits (61) subsequently treated with endotoxin.Prophylactic immunizations with monoclonal an-

.""{((,'-'

~

366 SURGERY, Gynecology & Obstetrics. April 19!

tibodies to cachectin/TNF protected baboonsagainst the lethal consequences (62) and manyof the metabolic consequences of severe bac-teremia (63). Furthermore, the cachectin/TNFblockade also attenuates the appearance of cir-culating interleukin-lp and interleukin-6 that isnormally seen in severe bacteremia (63). It istherefore proposed that antagonists of this cyto-kine mar be useful in combating both septicshock and the cachexia of disease.

l~~~~~;:7Described initially as a comitogen for the pro-

liferation of T lymphocytes, interleukin-l (IL-l)has had many functional descriptors, includinglymphocyte-activating factor, endogenous or leu-kocytic p}Togen, leukocyte endogenous mediator,osteoclast-activating factor, B-cell stimulatory fac-tor, catabolin and proteolysis-inducing factor,among others (64). IL-l is now known to includeat least t\vo proteins with only limited aminoacid homology (30 per cent) (65). Named IL-lIX and p, these t\vo proteins correspond to thepre'~ously described acidic (pI 5) and neutralforms (pI 7). .

IL-l is synthesized predominantly by bloodmonoc}'tes and tissue macrophages, but is alsoproduced by a variety of other types of cells,including endothelial cells, keratinocytes, bloodneutrophils and B lymphocytes (64). Like cachec-tin/TNF, newly synthesized IL-l IX and p existinitially as high molecular weight forms of ap-proximately 33 kilodaltons. The high molecularweight precursor form of IL-IIX is bioactive andis readily degraded to the 17 kilodalton formthat exists principally in a membrane-bound form(66). This presence of a cell-associated form ofIL-l can explain the capability of activated mac-rophages to induce natural killer cell cytotoxicity,T -cell proliferation and other functions by cellularcontact in the absence of any releasable IL-l

(67,68).By contrast, the 33 kilodalton precursor ofIL-lp

does not appear to be bioactive (69). As muchas 80 per cent of the newly synthesized proteinis retained intracellularly in the cytosolic poolas the precursor form and only 20 per cent isfurther processed and released. However, the IL-lp precursor is readily degraded to ilie 17 kilodaltonprotein by trypsin, plasmin and oilier nonspecificproteases (70). Cell death and lysis, the microen-vironment of the wound, contains sufficientpro tease activity to process spontaneously the IL-lp precursor into its lower molecular weight activeformo

~

.Volume 170

Although IL-1 a and ¡:i share limited aminoacid homology, fue two proteins bind \\rith equalaffinities to the IL-1 receptor (71). At least t\voclasses of IL-1 receptors have been described; bothtrPes. arrear to be high affi~\~ receptors (Mi-chaehs constant ofless than 10 moles per liter),but tissue distribution varies (72). The numberof receptors per cell varies bet\veen 100 and 10,000,but does not correlate \vith bioactivity. Receptorbinding by IL-1 a or ¡:i is followed by internaliza-tion and migration of fue ligand to fue nucleusof the cell, where these cytokines becomechromosome-associated (73). Receptor bindingand internalization contribute significandy to theclearance of these molecules. Like cachec-tin/TNF, both IL-1 a and ¡:i have short circulatinghalf-lives, in the range of six to ten minutes (74).Circulating IL-1 is readily degraded in a varietyof tissues, particularly in fue kidney, liver andskin.

Detection of circulating IL-1 in patients hasbe en complicated by fue fact that bioassays forIL-1 have relied on the ability of this proteinto stimulate proliferation of lymphocytes. Theresults of recent studies ha\'e demonstrated, how-ever, that other cytokines, such as IL-2, IL-4 andIL-6, can serve as mitogens for T <ell blastogenesis(75, 76). Furthermore, the results of recentstudies using sensitive immunoassays for IL-1 aand ¡:i (radioimmunoassays and EilSA) have failedto confirm the frequent appearance of IL-1 inthe circulation of individuals with inflammationthat was reported in original bioassays.

At present, IL-1a has not been detected inthe circulation of patients \\ith disease, and detec-tion of circulating IL-1¡:i has Qeen only sporadic.In fue results of one study (77), circulating IL-l¡:iwas observed only in four of 18 patients withmeningococcal sepsis; patients with detectable IL-1 died. lL-l¡:i has been observed more frequendyin children with septic purpura (78) and in in-dividuals with rheumatoid arthritis (79) or Ka-\vasaki's syndrome (80). II.r1 a or ¡:i could not bedetected in the circulation of human volunteerswho received endotoxin intravenously, whereastumor necrosis factor-a and IL-6 were readilydetected (81, 82). The absence of circulatingIL-1a during inflammation is consistent with itsprimary role as a membrane-bound cytokine prin-cipally involved in local paracrine and autocrine

regulation.IL-1 has been sho\\'ll to act on a variety ofimmunologic cells. In response to mitogenic andantigenic stimulation, T cells proliferate at ac-celerated rates in fue presence of IL-1. II.r1 stimu-

,'~:!i,;

~

Fong!ates T -cell proliferation by both inducing productionof IL-2 as well as by increasing the number ofIL-2 receptors on the T cell (83). In addition,IL-1 induces a rapid and sustained release ofboth mature and immature granulocytes fromfue baile marrow (34) and precipitates an influxof granulocytes into an inflammatory site in ,~vo .

(84). Although the results of earlier studies sug-gested that IL-1 might directly stimulate neutro-phil antimicrobial functions (85), such as neutralpro tease release and superoxide generation, theresults of more recent studies have ShOWI1 thatother cytokines, particularly cachectin/TNF (86,87), are more intimately involved in activatingblood neutrophils.

Recent evidence suggests IL-1 plays a significantrole in promoting myelopoiesis. IL-1 is a stronginducer of granulocyte/macrophage colony-stim-ulating factor (GM-CSF), macrophage-CSF (M-CSF)and CSF-1 release (88, 89), and is homologouswith the early erythroid differentiation factor,hemoprotein-l (91). The results of in vivo studieshave ShOWI1 that healthy animals receiving IL-1have a significant leukocytosis (34) and havemarkedly increased numbers of myeloid precur-sors in the baile marro,." (91). Neutropenic micealso show more rapid restoration of normalperipheral leukocyte counts after receiving IL-1(92) and the efficacy of restoration is equivalentto or greater than that seen with the administra-tion of CSF.

Neutropenic mice given IL-1 are less susceptibleto gram-negative infections (92-94), and this im-proved survival characteristic appears to be in-dependent of either IL-6 or neutrophil functionper se (92, 93). Pretreatment with IL-1 also in-creases the antimicrobial activity in protein-mal-nourished rats, rats subjected to a portal cavalanastomosis or rats that had splenectomy (95,96). The improved sequestration of bacteria inimmunosuppressed rats by IL-2 treatment resultsfrom increased bactericidal functions of Kupffercells and blood macrophages (96, 97). Micepretreated with IL-1 are al so less susceptible tothe lethal effec.of ionizing radiation (98). Thisradioprotective effect, ,."hich is shared with TNFbut not with IL-6 (99), appears to result, at leastin part, from the capability of IL-1 to inducecycling by myelopoietic precursors in the bonemarrow (100).

IL-1 exhibits complex actions in the centralnervous system. It induces rever by stimulatinga local release of prostaglandins in the anteriorhypothalamus (101) and induces anorexia by act-ing directJy on the central satiety center (102).

el al.: BIOLOGIC CHARACfERISTICS OF CYTOKINES 367

IL-1 intensifies the frequency and duration ofslo,,'-wave sleep seen during illness (103, 104), andattenuates the perception of pain after injury orinflarnmation by increasing the release of l3-en-dorphins (105) and increasing the number ofopiate-like receptors in the brain (106).

This cytokine algo appears to have majar met-abolic effects, particularly on the balance ofproteins in hepatic as well as peripheral tissues.The administration of IL-l induces hypoferremiaand hypozincemia both by increasing the releaseof proteins that bind trace minerals (107) aswell as by stimulating the uptake of zinc andiron into the hepatic reticuloendothelial system(108). Like IL-6 and, to a lesser extent, cachec-tin/TNF, IL-l is a principal inducer of hepaticacute phase protein synthesis (109, 110). Theproducts of synthesis of this class of proteinsand glycoproteins play important roles as proteininhibitors, local immune modulators and scav-engers for trace minerals and free radicals. Al-though IL-1 does not appear to modulate theprotein balance in skeletal muscle directly (111,112), the administration of this cytokine inducesskeletal muscle protein wasting in vivo (42). Theevidence is clear that IL-1 is irívolved in remodel-ing of connective tissue and bone during injuryand inflammation, stimulating the activity of os-teoclasts in bone (113) and degradation of col-lagenase and proteoglycan in connective tissue(114).

This pluripotent peptide no doubt exerts im-portant beneficial influences during injury. How-ever, inappropriate synthesis of IL-1, producingconsiderable pathologic conditions, has algo beensuggested. For example, one function of IL-1 isto increase the permeability of endothelial cells,permitting leukocytes to exit the vasculature andmigrate to inflammatory loci (115). However,when this process is excessive, as with a simul-taneous TNF-a release, excessive margination ofactivated neutrophils into pulmonary epitheliumcan contribute to pulmonary failure. In addition,excessive IL-1 release stimulates endothelial cellprocoagulant activity and in creases leukocytebinding but decreases heparin sulfate binding(116) to endothelial cells, thus promoting thelikelihood of a disseminated coagulopathy.

Olronic release of II.r 1 has also been implicatedin the pathogenesis of a variety of degenerativediseases, including rheumatoid arthritis (117), ca-chexia caused by cancer (118) and atherosclerosis(70). II.r1a gene transcription is augmented inspleens and nunors of mice bearing a transplan tablemeth)1cholanthrene-induced sarcoma (119). This

~~

.

~~

368 SURGERY, cynecology & Obstetrics. April 19!

chronic production of IL-1, as well as of cachec-tin/TNF, mar be central to some componentsof fue anorexic, weight loss, anemic and hepaticacute phase responses seen in these animals.

It is hoped that better understanding of thebiologic activities of this protein and its appear-ance in injury ,viII not only facilitate harnessingthe beneficial actions of this cytokine, but alsoallow selected use of antagonist therapy in coun-teracting its detrimental effects. IL 1 mar be po-tentially useful as an immune adjunct in protein-malnourished patients and for myelostimulation ll1leukopenic patients, such as those ,vith sepsis. Anti-bodies to IL-1 mar al so be therapeutic for fuechronic cad1exia in disease.

~~~~~~~;=)IL-6 is a family of at least six differentially mod-

ified phosphoglycoproteins (120, 121). This cyto-kine was isolated independently for its multiplebiologic properties and was initially described asl3c¡-interferon, hepatocyte-stimulating factor, B-celldifferentiation factor BSF-2 and hybridoma growthfactor (122, 123). The mRNA for this cytokineis expressed constitutively in numerous tissues,including fibroblastS (124), monocytes (125) andcertain types of malignant cells (19). Tran-scription and production of this protein in fibro-blasts, monocytes, macrophages, keratinocytesand endothelial cells are enhanced in vitro inresponse to other inflammation-associated cyto-kines (cachectin, IL1, lymphotoxin, platelet-derivedgrowth factor) as well as in response to virusesand such bacterial products as LPS (126). In-creased transcription of mRNA for this proteinby fibroblasts can be detected within 30 minutesafter LPS stimulation and is sustained for at least20 hours. A specific receptor for this c)rtokinehas been iden tified and cloned (127). IL-6secreted by human monocytes or fibroblasts con-sists of a family of glycoproteins with molecularweights ranging from 23 to 30 kilodaltons (120),although the prevailing circulating form inhumans after endotoxin challenge appears to bea 45 kilodalton species (82). The biologic sig-nificance of multiple forms of this protein isunder investigation, and it appears that thevarious molecular weight forms mar have \'ariedpotency in stimulating acote phase protein re-sponses and antiviral effects.

Like cachectin/TNF, IL-6 appears to be rapidlyreleased into the circulation in response to injury.It can be detected in the circulation of volunteerswithin 60 minutes of an intra\'enous bolos ofendotoxin (82). Additionally, circulating amounts

~ .Volume 170

of this cytokine are found both in experimentalinjury and in human disease. It is detected inthe circulation of tumor-bearing rodents (128).It is algo detected in patients after elective biliaryoperation (129) , in thermally in jured patien ts(130), in patients suffering acute bacterial infec-tions (131) and during renal allograft rejection(132). Circulating IL-6 are algo detected inpatients with meningococcal septic shock, inwhom high levels correlate ,vith death (77).

The biologic activities of this family of glyco-proteins in vitro are diverse. In fibroblasts, IL-6induces an antiviral state (122). Differentiationof lymphocytes is algo enhanced by this cytokine(133). Additionally, IL-6 stimulates proliferationof activated B cells and stimulates transcription andproduction of immunoglobulins in B cells (134).

IL-6 mar algo be important in the enhancedsynthesis of hepatic protein during injury. Inhepatocyte cultures, IL-6 promotes synthesis ofnumerous acute phase proteins, including C-reac-tive protein, serum amyloid A, fibrinogen, a1-antitrypsin, a1-antichymotrypsin and haptoglobin(135,136). These functions ofIL-6 are both over-lapping and complementary with IL-1.

The role of IL-6 in \ivo is under \igorous in-vestigation. This cytokine is an endogenouspyrogen that acts by way of fue production ofprostaglandins (137). In addition, levels of IL-6arrear to correlate ,vith the acute phase responsein patients ,vith burns (130), and this proteinis believed to be important in this reprioritizationof the synthesis of hepatic proteins after injury.It is unknown whether or not the cytokine affectsprotein balance in nonhepatic tissues.

Although elucidation of the exact role of thisc)rtokine in injury is incomplete, it is neverthelesslikely that IL-6 is an early and integral responderin the cascade of host mediators after injury. Incontrast to cachectin/TNF and IL-1, evidence thatIL-6 adversely influences cardiovascular stabilityor cellular integrity has not been found. Rather,the majar roles of this protein arrear to bebeneficial to the host by enhancing immune func-tion and acute phase protein synthesis.

'~~~~~~JIL-2 is produced by mitogen-stimulated or an-

tigen-stimulated T lymphocytes (138) and wasoriginally isolated as a T-cell growth factor. Ithas been purified, cloned and sequenced, andthe recombinant molecule has a molecular weightof 15 kilodaltons. The natural protein is variablyglycosylated (139). The recombinant nonglycosy-lated molecule has a serum half-life of six to

Fong

ten minutes when administered intravenously(140). The single disulfide bond between residues58 and 105 i~ essential for bioactivity (141). TheIL-2 receptor complex has algo been cloned; itis composed of a..o unlinked peptides of 55 and75 kilodaltons (142). Antigen stimulation of lym-phocytes triggers increased transcription of boththe IL-2 gene and the gene for IL-2 receptors(143). Binding with the receptor is followed byendocytosis of the IL-2 molecule (138) and in-tracellular degradation.

Unlike IL-1, cachectin/TNF and IL-6, whichare pleiotrophic, IL-2 appears to serve predom-inantly as an immunostimulant. The ability ofthis cytokine to activate lymphocytes for killingtumor cells in vitro and in vivo has been well-described (138). The use of this lymphokine ingenerating 1ymphokine-activated killer (LAK)cells is under investigation in the therapy ofmalignant disease (144). It is algo apparent thatthis peptide can promote host defenses againstinfection. In vitro, IL-2 not only induces T -cellproliferation, but algo enhances cell-mediatedcytotoxic T <eIl actions. Administration of IL-2 pro-tects mice against the lethality of intraperitonealadministration of Escherichia coli (145).

The production of IL-2 is impaired in lym-phocytes of animals and humans (146, 147) afterthermal injury. A variety of other human diseaseshave algo been associated with decreased en-dogenous production of IL-2, including cancer(148) and acquired immunodeficiency syndrome(AIDS) (149). Furthermore, impaired IL-2 pro-duction is correlated with increased mortalityafter a septic challenge in rodents, and ad-ministration of IL-2 to immunocompromised ro-dents confers survival benefit during subsequentinfection (147). It is thus hoped that IL-2 willbe a useful agent in restoring immune functionto immunocompromised patients, including thoseafter trauma and burns.

Increased secretion of IL-2 has algo been pro-posed to have a role in the acute responses toinjury. It has been noted that infusions of IL-2during chemotherapy against cancer produces al-terations in the homeostasis of the host, simulat-ing injury and endotoxemia (150). Although thismar suggest a role for this cytokine in the acuteresponses to infection, it must be noted thatdetection of the cytokine in the circulation duringactual infection or injury is rare, and circulatingamounts in injured humans and animals are ac-tually reported to be lower than in controls (151,152) and are substantially lower than levelsachieved during IL-2 infusions (150).

et al... BIOLOGIC CHARACTERISTICS OF CYTOKINES 369

Another setting in which Il.r2 and othef lym'-phokines have been proposed to affect the re-sponse to injury is that of pathologic conditions duringwhich intestinal bacterial flora are altered (153, 154).It is clear that the intestinal microflora influenceshost immune function (154, 155), including the func-tion of hepatic macrophages. The gastrointestinaltract, specifically the mucosal 1)'Inphoid tissuesand spleen, contai~s 50 per cent of the lymphoidtissues in the body (156) that are capable ofproducing such cytokines as 11.-2 and interferon-y.Disease and injury are often associated ,vith in-testinal rest or gastrointestinal dysfunction, withconsequent alterations in gastrointestinal bac-terial flora (157) and luminal antigens. Diseaseand intestinal rest mar algO increase intestinalmucosal permeability (158) and passage of lumi-nal antigens to intestinal lymphoid tissues. lt isproposed that increased production of 11.-2 andother cytokines by these lymphoid tissues mar,in turn, enhance local and systemic reticuloen-dothelial responsiveness. Our previous observa-tion that intestinal rest exaggerates some compo-nents of the systemic and splanchnic cytokineresponse to endotoxin would be consistent withsuch a hypothesis (153).

Because lL-2 is immunostimulatory, antibodiesdirected against lLr2 receptors have been proposedas potential immunosuppressive therapy duringtransplantation of organs. Results of experimentalstudies indicate that fuese receptor antibodiesmar protect cardiac allografts (159). Further-more, antibodies specific for the 11.-2 receptormar be protective in conditions of aberrant im-mune function, such as autoimmune diabetes mel-litus and systemic lupus erythematosus (160). Thus,this cytokine has important immunostimulatory func-tions that mar allow its use in immunocompromisedpatients. Antagonists to this cytokine mar algo beuseful as agents in clinical immunosuppressivetherapy. Although its role in adverse hemodynamicresponses to acute injury has been postulated,the direct role of this protein in eliciting detri-mental findings in clinical disease remains to bedemonstrated.

(~~~~;íJ~atural interferon-y (IFN-y) is a polymeric glyco-

protein that can be resolved to three monomericproteins of 25.0,20.0 and 15.5 kilodaltons (161),whereas the recombinant nonglycosylated proteinhas a molecular weigh t of 17 kilodaltons (162).Stimulated human lymphocytes, particularly hu-man helper T cells, readily produce IFN-y (163).Alveolar macrophages also arrear to he capab]e

370 SURGERY, Gynecology & Obstetrics. April 19~

of 'producing IFN-y (164, 165). Production ofIFN-y is uiggered by microbial antigens (166-168)or IL-2 (169). Increased transcription for IFN-yin T cells can be detected within six hours (170),and increased release of this protein peaks at ap-proximately 48 to 72 hours (166), but mar con-tinue for seven to eight days (163). RecombinantIFN-y has a half-life in the circulation of approx-imately 30 minutes (171).

Circulating amounts of this protein are de-tected in the serum of patients with malaria (172)and autoimmune diseases (173-175), as wellas in the cerebrospinal fluid of patients withmeningitis (176) or multiple sclerosis (174). Thiscytokine can algo be detected within injured tis-sues-for example, in the vesicular fluid of herpessimplex (177) or psoriasis (173), in fue lungs ofpatients with tuberculosis (179) and in the syno-,rial fluid of patients ,vith rheumatoid arthritis(180) .

IFN-y was originally described for its antiviraleffects. This C),tokine has protective effects againstother microbes, including bacteria, fungi andparasites (172). The antimicrobial effects involveacti,'ation of macrophages to increase respiratoryburst acti'rity (172, 181) and increased killingacti'ity (181-183). The populations of macro-phages that are activated by IFN-y include notonly circulating monocytes, but algo alveolar mac-rophages, human peritoneal macrophages (184)and murine Kupffer ceIIs (186).

Infusion of IFN-y into patients enhances oxida-tive acti,ities of bIood monocytes (186, 187). Inpatients with cancer, administration of IFN-yproduces enhanced cytotoxity of circuIatingmonoC)'tes toward tumor ceIIs in vitro (188). In-fusions of IFN-y have been associated \\ith fever,myalgia and headache. IsoIated reports of h)per-triglyceridemia (189) and hepatic impairment(171, 190) ha\e also been reported, but are notbeIieved to be important effects of the naturaIlysecreted protein in vivo. It is hoped that thecytokine wouId be usefuI as macrophage-activat-ing therapy in immunocompromised patients,such as those with sepsis, tumors, AIDS, or otherinfected patients.

GRA. 'l;l"LOCYfE/!\1.-\CROPfMGECOLO~\:STI!\fl"L-\TI~G FACTOR

CoIony-stimuIating factors (CSF) are a familyof glycoproteins that were isolated for their po-tential to stimulate formation of coIonies of gran-uIoc).tes or macrophages in \itro, and includeef).thropoietin, interleukin-3 (IL-3), granulocyte-CSF (GCSF), macrophage'(;sF (M-CSF) and gran u-

10 .Volume 170

locyte/macrophage CSF (GM.(:sF). GM.(:sF is a glyco-protein with a molecular weight of 22 kilodaltons,consisting of 141 amino acids in mice and 144amino acids in humans. There is a 50 per centhomology bet\4/een the rodent and the human mol-ecule, )'et the actions of this protein are species-specific. GM-CSF is a product of acti\'ated Tcells, macrophages and endothelial cells. Itsproduction is induced by LPS and IL-2 (191).A high affinity receptor exists for this cytokineand is expressed in granuloC)'te and macrophageprogenitor cells, as well as matute myeloid cells,such as neutrophils, macrophages and eosinophils(192, 193).

GM-CSF stimulates formation of colonies ofneutrophils, macrophages and eosinophils invitro (194, 195). GI)'coS)1ation of GM-CSF doesnot arrear to be necessary for biologic activity,because the recombinant bacterial product, whichis nonglycosylated, also induces leukocytosis inprimates (196). In addition to its myeloprolifera-tive effects, GM-CSF al so activates neutrophils in\~tro (197-200). Howe\'er, no improvement inneutrophil function in response to GM-CSF hasbeen reported in clinical trials.

Infusions of human G~1-CSF into primates pro-duce leukocytosis (201) that in\'ol\'es neutrophils,lymphocytes, monocytes and eosinophils. Thiscytokine and other CSF ha\'e been proposed tobe clinically useful in promoting myeloprolifera-tion in leukopenic clinical settings, such as AIDS,transplantation of bone marrow and sepsis. Ina primate model of autologous bone malTOW trans-plantation, primates that recei\'ed GM-CSF withtransplantation after irradiation of the entirebody had significantly higher leukocyte countsthan did controls that were not treated \\ith GM-CSF (202). Treatment ofpatients who undel14/ent bonemarrow transplantation has demonstrated a dose-dependent impro\'ement in leukOC)'te count. Themajor toxicities of this protein in \i\'o include fever,m)'algia and possible renal and hepatic impair-ment (203-205).

~ODU~ON OF CYTOKI~ES I~! ~

:=1;:~=~=ili; production ~f cytokines in vivomar occur in a variety of tissues. Gene transcrip-tion for cachectin/TNF is increased at numeroussites after injection of endotoxin in rodents (206),including liver, kidney, lung and spleen. Genetranscription for IL-1 is also increased after injuryat many tissue sites (207). Additionally, endotoxininfusions in humans elicit production of cytokinesnot only by circulating monoc}'tes but also bysplanchnic tissues (23).

~~

FongProduction of cytokines at the various sites mar

be different, depending on the location of theinjurious stimulus. In meningitis, for example,levels of cachectin/TNF (208) or IL-6 (131) aredecidedly higher in the cerebrospinal fluid thanin the systemic circulation. IL-1 and IL-6 arealgO found locally in healing wounds (209). Ad-ditionally, intratracheal administration of LPS inexperimental models is associated with significantincreases in the amounts of TNF in the fluidfrom bronchoalveolar la\rage, but without detectionof this cytokine in the circulation, while ad-ministration of LPS intravenously increases cir-culating amounts without affecting the levels inthe fluid from bronchoalveolar lavage (210).

The notion that cytokines are produced in var-ious tissues is supported by the finding of cell-associated forros of cachectin/TNF (9, 10) andIL-1a (66). These forros mar be important in 10-calized biologic effects of cachectin/TNF throughcell to cell interactions. Hence, concentrationsof these proteins in tissues are likely more biologi-cally significant than amounts detected in thecirculation. Production of cytokines at many sites,particularly tissue production at sites of injury,suggest important local paracrine effects for theseproteins. Furthermore, cytokines produced in spe-cific tissues mar spill into the systemic circulationand exert additional endocrine effects.

INTERACTIONS A.\{ONG MEDL-\TORS

Cytokines elicit release of other mediators andare likely important in propagating the hostmediator cascade during injury. Cachectin/TNF,for example, elicits the release of fue counter-regulatory hormones glucagon, cortisol and epi-nephrine in vivo (59). In a primate model of bac-teremia, fue release of these hormones and thecytokines IL-1¡3 and IL-6 could be blocked bythe administration of antibodies specific forcachectin/TNF (62, 63). Cachectin/TNF alsoelicits release of prostaglandin E2 (211), IL-1,GM-CSF (212) and cachectin/TNF itself (213).IL-1 acts on the neuroendocrine axis, stimulatingthe release of pituitary neurohormone, includingadrenocorticotropic hormone, thyroid-stimulatinghormone and somatostatin (214-216). IL-1 alsodirectly elicits adrenal corticoid (217) release andpancreatic release of both insulin and glucagon(218). IL-6 can elicit production of IL-2 in vitro(133) and IL-2 can elicit increased translation ofcachectin/T~F mR..~A and protein in alveolarmacrophages (219) and increased production ofcachectin/T~F by human monocytes in vitro(220) .

et al.: BIOLOGIC CHARACfERlSTICS OF CYTOKINES 371

C)'tokine mediators algo exhibit synergy amongthemselves as well as with other endogenousmediators. For example, cachectin/TNF enhan.ces the glucagon-mediated uptake of amino acidsby the liver (47). The synergistic interaction ofcachectin/TNF and IL-l in many types of tissues,including pituitary cells, bone, vascular endothe-lial cells, skin fibroblasts and islets of Langerhans,

.are well-described (64). Cachectin/TNF is syner-gistic \\7Íth IFN-y in their antiproliferative effectson certain human and murine cell liDes (221)and in their enhancement of fungus-killing bypol)'ffiorphonuclear ceIls (222). Cachectin/TNFis algo synergistic with CSF in macrophage pro-liferation (223). Systemically, combined infusionsof cachectin/TNF and IL-l into conscious rabbitsproduce hemodynamic instability, alterations inexpenditure of energy and hypertriglyceridemia,whereas infusions of each cytokine atolle at com-parable clases yield only minimal effects (224).

The mechanism for such synergism amongcytokines mar involve an increase in both thenumber of cytokine receptors and receptor bind-ing affinity. IL-6, for example, increases the ex-pression of IL-2 receptors on thymocytes (225).GM-CSF increases the expression of receptorsfor IFN-y (226). IFN-y, in turn, increases surfaceexpression of IL-2 receptors on human monocytes(227). The binding of the cachectin/TNF toadipocytes and fibroblasts is known to be en-hanced by pre-exposure of the ceIls to IFN-y(228) .

The postinjury cascade of endogenous media-tors not only express some redundancy and syner-gism of function, but also appear to be triggeredand amplified in a complex, interdependent man-fiero Hence, the entire rnilieu of hormonal and cyto-kine mediators must be considered in the assessmentof postinjury biologic response.

SU~MARY

Cytokines are integral to normal homeostasisand to the response to injury. The biologic ac-tivities and synergistic actions of these proteinscontinue to be elucidated. In moderate quan-tities, these proteins likely confer such beneficialeffects as myelostimulation, activation of immunecells and reprioritization of metabolic processesto provide substrates important in combating theresults of injury. Exaggerated or prolongedproduction of these proteins, however, marproduce detrimental effects that lead to a pooroutcome. Specific antagonists against cytokinesoffer potential therapy in these mstances of aber-rant cytokine response.

~!;j~

372 SURGERY, Gynecology & ObstRtriCS. April 1990. Volume 170

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~~

~l~:

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374 SURGERY, Gynecology & Obstetrics. April 1990 .Volume 170

80. ~1:Au"RY, C. P.J.,SALO, E., and PELKONEN, P. Circulating 98. NETA, R, DouaIFs, S., and OPPFJ\'HElM, J. J. Interleukin 1mterleukin-l¡:l in patients with Kawasaki disease. N. is a radioprotector.J. lmmunol., 1986, 136: 2483-2485.Engl. J. Med., 1988, 319: 1670-1671. 99. NETA, R" VOGEL, S. N., SIPE,J. D., and others. Compar-

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