Interleukins and tumor necrosis factor in inflammation.

Volume 28, Issue 1 (1990)

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lnterleukins And Tumor Necrosis Factor in Inflammation

Critical Reviews in Clinical Laboratory Sciences Downloaded from informahealthcare.com by University of British Columbia on 12/09/14 For personal use only.

Jeffrey S. Warren

ABSTRACT Intense research efforts have been directed toward characterizing mediators that control the inflammatory response and regulate the growth, differentiation, and function of cells involved in inflammation. Tumor necrosis factor, or cachectin, and members of a heterogeneous group of peptides called interleukins exhibit a wide spectrum of activities, some of which appear to influence the evolution of inflammatory processes. This review outlines the observations that have led to our current understanding of the biology of tumor necrosis factor and the interleukins. Particular attention is directed toward the evidence suggesting that these cytokines function as mediators of inflammatory responses. Key Words: Tumor necrosis factor and interleukins 1, 6, and 8.

1. INTRODUCTION The inflammatory response is an exquisitely regulated process that occurs in the microcirculation and is characterized by the accumulation of both cellular and chemical mediators at the site of insult. The classic manifestations of acute inflammation -redness and swelling with heat and pain - have been recognized for nearly 2000 years. It has been only in the last century that such fundamental participants as phagocytes and the complement system have been recognized as critical players in inflammatory states. Modem biochemical and immunological techniques have led to a more detailed mechanistic understanding of the events that trigger, perpetuate, and terminate an inflammatory response. For instance, detailed understanding of phagocytic cell functions, biochemical characteristics of complement proteins, and the biological significance of leukotrienes and oxygen radicals have all evolved in the last few decades. It has been even more recent that the identities and functions of peptide mediators called cytokines have become appreciated in the context of inflammation. The purpose of this review is to provide a state-of-the-art synopsis of important “inflammatory cytokines”. It should be noted at the outset that numerous biological activities have been attributed to these substances and that the “state-of-the-art” has advanced to a varied degree for each cytokine. Because of the breadth of information that has accumulated in this field, attention is directed toward the mediators thought to have important roles in acute inflammatory processes. Keeping in mind that there are many inflammatory mediators and that several substances discussed here harbor a variety of noninflammatory activities, tumor necrosis factor (TNF) and interleukins 1, 6, and 8 (IL-1, IL-6, and IL-8) are discussed.

J. Warren, A.B., M.S., M.D., Department of Pathology, M7524 MSRBI, The University of Michigan Medical School, 1301 Catherine Street, Ann Arbor. Michigan 48109.

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Critical Reviews in Clinical Laboratory Sciences


II. HISTORICAL PERSPECTIVES A. Tumor Necrosis Factor Our understanding of TNF evolved from three convergent lines of investigation, a fact reflected by the TNF synonym, cachectin. Based on studies conducted in the 1940s and 1950s, it was thought that the pathophysiologic derangements of Gram-negative sepsis and endotoxic shock were attributable to the direct toxic effects of endotoxin (lipopolysaccharide, LPS) on cell function.’-2In 1968, Sultzer observed that C3WHeJ mice failed to exhibit signs of shock following endotoxin admini~tration.~ Subsequent studies revealed that C3WHeJ mouse lymphocyte^,^ fibroblast^,^ and macrophages did not exhibit their usual LPS-induced It became clear that the LPS resistance seen in C3WHeJ cells is a heritable trait.8 Conversely, C3WHeJ mice could be made LPS responsive by transplanting C3WHeN bone marrow cells (LPS-response strain) into irradiated mice.g These studies provided evidence that LPS responsiveness is a genetic property expressed by hematopoietic cells. More recent work has demonstrated that many of the pathophysiologic manifestations of LPSinduced shock are due to the endogenous secretion of TNF. In 1975, Carswell et a l . I o reported that infusion into mice of LPS-induced shock serum, which was obtained from animals previously “primed” by injections of Bacillus CalmetteGuerzn, could induce hemorrhagic necrosis of solid tumors. From this observation, the term “tumor necrosis factor” was born. Several groups later demonstrated that TNF is chiefly a product of monocytes and macrophages and that it could lethally injure some types of tumor cells in vitro.’O-’* More than 100 years before, Coley had described hemorrhagic tumor necrosis following the administration of bacterial products. l 3 Subsequent studies revealed that LPS was the bacterial component responsible for this phenomenon.14-’8In the early 1960s, O’Malley et a1.I9 showed that serum obtained from mice injected with LPS could cause necrosis of transplanted solid tumors in recipient animals and that the LPS-inducible activity disappeared from the serum within a few hours of its appearance. Although the precise mechanism(s) of in vifro TNF-mediated tumor necrosis are not fully understood, there is some evidence that ischemia is important.” This conclusion is supported by the observation that some tumors are susceptible to necrosis when in the solid form, yet resistant when maintained in ascites as a single cell suspension. The third line of investigation relevant to TNF derived from studies of the pathogenesis of cachexia. Several investigators recognized that rabbits chronically infected with Trypanosoma brucei exhibited hypertriglyceridemia late in the course of the infection.21*22 Because such a metabolic alteration would be unexpected in a state of malnutrition, this aberration was termed “paradoxical hypertriglyceridemia” . Ultimately, paradoxical hypertriglyceridemia was linked to the systematic suppression of lipoprotein lipase (LPL) a~tivity.’~ Blockade of LPL prevents adipocytes and other cells from catabolizing, and thus storing, fatty acids contained in trigl y~e ri de s.~~ The serum factor responsible for systemic LPL suppression was named “cachectin” . More recent amino acid and cDNA sequencing studies have proven that cachectin is, in fact, the same molecule as TNF.2’-29The availability of recombinant TNF has been critical in defining its biological activities both in vivo and in vitro. This perspective illustrates the multifunctional nature of TNFkachectin and emphasizes how seemingly different lines of investigation uItimately led to a common endpoint. 6. Interleukin 1 Interleukin I (IL-I) is a pivotal mediator of the host’s response to microbial invasion, immune reactions, and i n f l a m m a t i ~ n .As ~ ~in , ~the ~ case of TNF, our present understanding of IL-I evolved from several lines of investigation. It has been very recently that two biochemically distinct but structurally related IL- 1 molecules (IL-1 alpha and IL- 1 beta) have been cloned and expressed. 32,33 Nevertheless, the earliest recognition of the existence



39

of an endogenous substance now known as IL-1 came from studies conducted by Menkin and Beeson during the 1940s. These investigators observed that activated peritoneal exudate cells released a soluble factor that triggered a fever response when injected into animals. Because neutrophils were the predominant cell type present in peritoneal exudates, the term “granulocyte pyrogen” was applied to describe this f a ~ t o r . ’Subsequent ~ studies revealed that granulocyte pyrogen was a protein and that a similar substance could be isolated from the bloodstream of rabbits following injection of infectious agents or e n d ~ t o x i n .The ~~.~~ circulating pyrogen became known as “endogenous pyrogen” (EP), a term that can be found in textbooks published in this decade. Studies in the 1960s and early 1970s established the role of EP in the pathogenesis of fever observed in a wide spectrum of inflammatory and immunologic diseases .37.38 Beginning in the late 1960s, Kampschmidt and others began characterizing a substance called ‘‘leukocytic endogenous mediator” (LEM).39,40 Leukocyte endogenous mediator was derived from phagocytic cells and was shown to trigger a series of metabolic perturbations associated with the acute-phase response. Infusions of LEM resulted in granulocytosis and increased synthesis of several serum proteins, including ceruloplasmin, C-reactive protein, haptoglobin, and f i b r i r ~ o g e n . Biochemical ~’~ analysis and physiological studies strongly suggested that EP and LEM were identical or closely related molecule^.^^,^^ Much of the work in the 1970s centered around purification and characterization of these two activities. A variety of in vivo bioassays were developed that led to a more detailed understanding of the physiological and pathophysiological roles of EP/LEM in various inflammatory states. Studies by Dinarello, Wolff, and others led to the recognition of EP/LEM as a heterogeneous 12,000- to 17,000-Da protein produced primarily by mononuclear phagocytes rather than n e u t r o p h i l ~Many . ~ ~ ~ of ~ the studies that began to define mechanistic roles of EP/LEM in inflammation and immunity were direct outgrowths of these studies. In 1972, lymphocyte-activating factor (LAF) was described. Studies by Gery and Waksman revealed that LAF could potentiate thymocyte proliferative responses to suboptimal concentrations of plant l e ~ t i n sThe . ~ ~recognition that sensitized lymphocytes and immune complexes play a role in the induction of EP-associated mechanisms of fever with immunologically mediated disease processes. These investigators not only emphasized that mononuclear phagocytes are the chief source of LAF, but they also provided critical data supporting the concept that mononuclear phagocytes participate in the induction of immunity by secreting soluble factors required for T lymphocyte activation. Biochemical characterization of LAF revealed marked similarities to EP/LEM. By the beginning of this decade, most investigators presumed that LAF, EP, and LEM were either the same molecule or at least members of a closely related family of molecules. Several other mononuclear phagocyte-derived products that had immunoregulatory activities were also later shown to behave identically to LAF (Table 1). Finally, at the Second International Lymphokine Workshop held in Switzerland in 1979, the term interleukin 1 was adopted to include LAF as well as EP, LEM, e t ~ . Since ~ * 1979, additional factors have been characterized that have subsequently been shown to copurify with LAF (Table 1). Two structurally related IL-1 molecules have been cloned and expressed: IL-1 alpha and IL-1 beta.32*33 The availability of recombinant IL-1 has been pivotal in arriving at our current state of knowledge regarding the roles of this monokine in inflammatory and immunologic processes.

C. lnterleukin 6 The ultimate recognition and characterization of interleukin 6 (IL-6) emerged from studies of the regulatory interactions between T and B lymphocytes in the antibody re~ ponse. It ~) was recognized in the 1970s that soluble cell-derived helper factors could replace intact T lymphocytes in the induction of B lymphocyte proliferation and antibody secretion.s4-57

40


Table 1 lnterleukin 1: Updated Nomenclature Synonyms and previous names


Granulocyte pyrogen Endogenous pyrogen (EP) Leukocytic endogenous mediator (LEM) Lymphocyte-activating factor (LAF) Mononuclear cell factor Catabolin Osteoclast-activating factor (OAF) Muscle proteolysis-inducing factor

Comments

Ref.

Subsequently renamed “endogenous pyrogen”; later shown not to be produced by granulocytes

31 47, 48

Shown to trigger granulocyte mobilization; triggers acute-phase response Potentiation of T lymphocyte response to mitogens Stimulates collagen and fibrinectin synthesis by rheumatoid synovial cells Triggers cartilage resorption Triggers osteoclast-mediated bone dernineralization Mobilizes amino acids from skeletal muscle

3941 42-44 49 50

51 31 31

Initially, this bioactivity was called T-cell-replacing factor (TIZF). Because it was thought that a single class of molecules was responsible for both T-cell-derived mitogenic activity and B cell differentiation, this activity was temporarily referred to as interleukin T5*However, experiments employing more highly T-cell-depleted B cell populations and the discovery of B cell-specific growth and differentiation factors made it clear that IL-2 alone could not replace the function of T cells in the antibody response.59 The development of human T lymphocyte hybrid clones that secreted B cell differentiation factor (BCDF), but not IL-1, IL-2, gamma-interferon, or B cell-stimulating factor (BSF-1 or IL-4), was instrumental in the recognition that regulation of B cell differentiation (high-rate antibody secretion) is controlled by a discrete factor.60*61 By 1983, the protein harboring BCDF activity was purified to homogeneity and designackd BSF2.62 In the last 5 years, the cDNAs for three distinct factors - BSFl (IL-4), BCGFII (IL-5), and BSF2 (L-6) - have been cloned and expressed, and the roles of these substances in B lymphocyte differentiation and function have been d e t e m ~ i n e d . It~ ~now ‘ ~ ~appears that IL-4 is a B cell activation molecule, IL-5 is a proliferation-triggering molecule, and LL-6 triggers ‘ ‘high-rate’’ immunoglobulin secret i ~ n The . ~ ~subsequent recognition that BSF2 mediates biological activities in a variety of different cell types led to the current designation, IL-6.53It should be emphasized that, like IL-1,IL-6 has had previous or alternative names based on its spectrum of activities (Table 2). It has been quite recent that potential roles for IL-6 in prototypic inflammatory processes have been addressed.

D. Interleukin 8 Several partially characterized monocyte and macrophage-derived peptides that exhibit neutrophil chemotactic or other activating activities have been recognized during the past 15 years. Beginning in the late 1970s, several groups reported that alveolar macrophages could release factors that are weakly chemotactic for n e ~ t r o p h i l s . Subsequent ~~-~~ studies involved biochemical analysis that led to the identification of a 6000-Da protease-sensitive factor termed “alveolar macrophage-derived neutrophil-activating factor” (NAF) and “alveolar macrophage-derived chemotactic factor” .81 This factor was reported to be weakly chemotactic for neutrophils and could not, by itself, trigger a respiratory burst by isolated neutrophils. Other investigators demonstrated that activated human monocytes could secrete at least two distinct “granulocyte-activating mediators” (GRAM) that weigh 60,000 and 10,000 Da, respectively, are trypsin sensitive, and trigger a delayed chemiluminescence response by neutrophil~.~’.~~ In 1986, Kownatski et al. described a potent, 10,000-Da chemotaxin derived from m o n o c y t e ~ .Yoshimura ~~ et d.recently described a similar monocytederived cationic neutrophil chemotactic factor.8s While it became clear that these activities

Hybridoma plasmacytoma growth factor (HPGE) Interleukin-HPI Hepatocyte-stimulating factor (HSF)

Interferon beta 2 (IFNp2)

26-kDa protein

B cell stimulatory factor 2 (BSFZ)

B cell differentiation factor (BCDF)

T-cell replacing factor (TRF)

Synonyms and previous names

Table 2 lnterleukin 6: Updated Nomenclature

T-Cell-derived hybridoma growth factor Regulates the acute phase response in liver cells

Same as 26-kDa protein; shown to have no antiviral activity

(Imp21

Soluble T-cell-derived factors that promote B cell proliferation and antibody secretion Confirmed by the establishment of BCDF-producing human T hybrid clones Designated “BCDF” until N-terminus sequence data in 1983 Originally induced in human fibroblasts; an interferon

Comments

73, 74 15 6 , 11

70-72

69

67. 68

60, 61

54-57

Refs.


c


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are distinct from TNF and IL-I, the lack of amino acid sequence data has made their relationship to IL-8 unclear. Biochemical and functional differences have been reported, but it is conceivable that several of these NAF-llke or IL-8-like factors are identical. Recently, several groups have obtained definitive structural data and preliminary functional data that have led to the current definition of neutrophil-activating peptide-1 (NAP-]), neutrophil-activating factor (NAF), granulocyte chemotactic peptide (GCP), and monocytederived neutrophil chemotactic factor (MDNCF). Protein sequence data, in conjunction with cDNA sequence data, have shown that NAF, NAP-I, GCP, MDNCF, and the so-called “310 C” cDNA clone refer to the same molecule (IL-8) and that this peptide bears sequence homology with beta-thromboglobulin and platelet factor 4.86-90 Although there appear to be very minor structural variations within naturally occumng IL-8, the availability of recombinant IL-8 should provide a means of defining its biological activities in inflammatory processes.

111. BIOLOGY OF CYTOKINES INVOLVED IN ACUTE INFLAMMATION A. Tumor Necrosis Factor The predominant “mature” form of TNF has a molecular weight of approximately 17,000 Da.26 Amino acid sequence analyses of human, mouse, and rabbit cDNA clones indicate that mature TNF contains 154 to 157 residues and that the secreted form is derived from a prohormone bearing 70 to 80 additional amino acid residues.27-29*91-9s Although little is known about potential functions of precursor or partially processed species of TNF, it appears that given cell types secrete varying proportions of differently sized TNF species, depending upon the agonist employed to trigger cytokine release.96 The high degree of sequence homology (nearly 80%) among murine, rabbit, and human TNF suggests that this mediator is highly conserved and presumably explains the high degree of species cross-reactivity observed e ~ p e r i m e n t a l l y . ~Rabbit, ~ - ~ ~ mouse, and human TNF each contain two cysteine residues and murine TNF contains a single glycosylation ~ i t e .Intramolecular ~ ~ . ~ ~ disulfide bonds and carbohydrate moieties do not appear to be critical for bioactivity, since reduced TNF and nonglycosylated recombinant murine TNF (expressed in Escherichia coli)exhibit full functional a c t i ~ i t y . ~Controversy ’,~ centers around the mechanism(s) of TNF secretion. Tumor necrosis factor exhibits moderate overall hydrophobicity, but apparently does not possess the 20 to 30 amino acid hydrophobic leader sequence contained in many secreted peptides .91.92 Several investigators have described a membrane-associated TNF that may play a role in cell-to-cell or other short-range interactions.lW Several groups have also characterized a TNF molecule that contains an internal hydrophobic region that may allow it to span cell m e r n b r a n e ~ . ~ ~The . ’ ~relationship ’ between secreted and membrane-associated TNF remains to be clarified. There is in vitro evidence that TNF molecules can noncovalently associate to form multimers that more avidly bind receptors than monomers. 26.92.97.98.102 The physiologic significance of this phenomenon is also unclear. Specific, high-affinity (Kd = to 2 X lo-’’ M ) TNF receptors have been identified on a wide variety of cell type^.^^.^^^-^^^ Studies utilizing NH,-terminal deletion mutants suggest that the amino terminus of TNF is required for activity. 106*107 Scatchard analyses of different cell types indicate that individual cells may contain several hundred to several thousand TNF receptors. The molecular structure of the TNF receptor has not been resolved, but initial cross-linking studies have identified 75- and 90-kDa polypeptides and suggest that there may be as many as four polypeptide subunits per receptor. ’08-’l 2 F’reincubation of cells with gamma-interferon significantly amplifies the number of cell surface receptors for TNF.113,114 Similarly, while resting lymphocytes do not possess surface TNF receptors, recent studies have shown that



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activated human peripheral blood T lymphocytes do express TNF receptors. 'I5 Cytotoxicity studies utilizing a variety of tumor cell lines indicate that specific binding sites are necessary, but not sufficient for cells to be sensitive to TNF-mediated l y ~ i s . ~ Little ' is currently known about TNF receptor-transduction mechanisms except that receptor-bound TNF is internalized and degraded. 'O3.*O5 Regulation of TNF gene expression is just beginning to be addressed. The TNF gene appears to be linked to the major histocompatibility complex in both humans and mice.'16.''7 In humans, the TNF gene is located near the HLA-B and HLA-C Synthesis of TNF appears to be regulated at both the transcriptional and posttranscriptional levels. The most compelling bits of evidence for tight transcriptional control are derived from nuclear runoff studies showing that there is augmented mRNA synthesis by nuclei that have been isolated from LPS-stimulated macrophages and that corticosteroids and PGE, can block this LPS-triggered response. '19-121 Most of the data relevant to posttranscriptional control of TNF production center around the observation that there is a highly conserved AU-rich RNA segment located at the untranslated 3' end of TNF mRNA molecules.'22 The presence of this AU-rich sequence correlates with an increased rate of mRNA degradation by specific intracellular nucleases .i22.123 The same AU-rich regulatory region has been identified in transcripts that encode other inflammation mediators and several oncogenes. 1 2 2 ~ 1 2 It 4 is possible that the message instability conferred by such AU-rich regions of mRNA constitutes an important protein synthetic control mechanism. It is plausible that the number of AUrich regulatory elements associated with a given mRNA species plays an important role in orchestrating the magnitude and duration of a given cellular response.

B. Interleukin 1 Molecular cloning studies have confirmed the existence of at least two distinct, but related IL-1 molecules: IL-1 alpha and IL-1 beta.32,33As in the case of TNF, the predominant secreted form of IL-1 has a molecular weight of approximately 17,500 Da. Despite their similar sizes and the considerable overlap in biological activities, IL-1 and TNF are not structurally related. Interleukin- 1 alpha and beta share relatively little amino acid homology - approximately 26% in humans. While there is a modest degree of overall homology between IL-1 alpha and L - 1 beta, there are five homologous regions, designated A, B, C, D, and E.32,125*'26 Structure-function studies utilizing synthetic peptides and amino acid deletion mutants suggest that the C and D homology regions of IL-1 alpha and IL-1 beta contain the necessary residues for IL- 1 receptor binding. Interleukin 1 receptors equally recognize IL-1 alpha and beta, and both IL-1 species exhibit the same spectrum of biological activities. Like TNF, IL-1 lacks a distinct cleavage sequence and a large proportion remains cell associated.127Interleukin 1 (alpha and beta) is synthesized as a 31,000-Da precursor molecule that is processed into a cell-associated 22,000-Da form, the 17,500-Da secreted form, and a variety of smaller extracellular species ranging down to 2000 Da. 127.128Processing of IL-1 appears to occur through the action of several serine proteases, including elastase, trypsin, and plasmin.'27.'28Although the 31,000- and 22,000-Da forms of IL-1 are clearly cell associated, their precise relationships with the cell membrane are debated. Several investigators have demonstrated a membrane-associated form of IL- 1 , but given the lack of a hydrophobic leader sequence the exact location and orientation of this form remains unresolved and controversial. 129.130 Most of the membrane-associated IL- 1 is the alpha form, while the predominant secreted form i s IL- 1 beta. Membrane-associated IL- 1 is thought to play a role in autocrine and paracrine events as well as in localized processes such as antigen presentation. Receptors for IL-1 have been identified on a number of different cell types, but they appear to be heterogeneous and their affinities do not invariably correspond with the magnitude of the cellular r e ~ p o n s e . ' ~ ' .An " ~ 80,000-Da IL-1 binding protein (Kd>5 X lo-''

44



M ) has been identified on several cell lines and has recently been cloned in the mouse

system. 135 The cloned IL-I binding protein has a molecular weight of approximately 65,000 Da - the discrepancy with purified 80-kDa proteins apparently attributable to the absence of glycanase-sensitive carbohydrate moieties. 136 The 65,000-Da murine IL- I binding protein contains a large extracellular domain, a 2 1-amino acid hydrophobic transmembrane segment, and a cytoplasmic domain.'35 This receptor is a member of the immunoglobulin gene superfamily and bears similarity to receptors for other growth factors, including platelet-derived growth factor, IL-6, and colony-stimulating factor-]. A class of higher-affinity (Kd = lo-', M) IL-1 binding sites, distinct from the cloned 65-kDa murine receptor, has been reported by several groups. L35.137-139It is unresolved whether this second class of IL-1receptors represents a discrete set of molecules or whether the different binding affinities can be explained by the occurrence of 80-kDa receptor conformation changes, the existence of monomeric and polymeric forms, or a second, uncharacterized, subunit chain. As in the case of TNF, IL- 1 receptor-transduction pathways are incompletely understood. It appears that engagement of the so-called 80-kDa IL- 1 binding protein can initiate arachidonate breakdown and trigger a rise in cytosolic calcium, as has been described in a variety of signal-transduction systems. 134.140 However, recent studies suggest that low concentrations ( 10-13to M ) of LL- 1 can also trigger rapid cell responses through an unusual mechanism of phospholipid hydrolysis. Exposure of Jurkat cells (and other IL-1-responsive cell lines) to IL-1 results in a very rapid rise in diacylglycerol with no increase in inositol phosphate turnover or cytosolic calcium.'41 Since Jurkat cells have no demonstrable IL-1 receptors, it has been proposed that cell activation might occur through a glycosyl-phospholipid-anchored cell surface protein that is distinct from 80-kDa IL-1 binding protein. As noted previously, the structural relationship of this putative surface protein to transmembrane IL- 1 binding proteins remains speculative. The rapid responses of endothelial cells and some tumor cell lines to femtomolar concentrations of IL-1 tempts the invocation of such a transduction mechanism.134It must be emphasized that there is as yet only biological precedence and indirect experimental evidence for such a pathway. Regulation of IL- 1 gene expression occurs at the transcriptional and postranscriptional levels. The human IL-1 alpha and IL-1 beta genes are both located on chromsome 2 and each gene contains seven ex on^.'*.^^ In cells examined, mRNA coding for IL-1 beta predominates over mRNA coding for IL-1 alpha.31J42March et al. have suggested that preferential expression of pro IL-1 beta is attributable to the fact that the pro IL-1 beta gene promoter is 10- to 50-fold more efficient than that of the alpha gene. 142 This predominance of IL-1 beta is also observed for secreted protein in biological fluids. As in the case of TNF, understanding of IL- 1 gene regulation is rudimentary. Transcription for IL- 1 without translation can be initiated in monocytes by adherence to plastic surfaces.31 In contrast to cell adhesion, cell activation with LPS or through phagocytosis leads to increased transcription as well as translation and posttranslational processing. Under certain conditions, transcription for IL-1 can be enhanced by blocking the synthesis of a suppressor ~ r 0 t e i n . Transcription I~~ for IL-1 is retarded by PGE,-induced cyclic AMP production, the protein kinase C inhibitor. H7 (l-(5-isoquinolinylsuIfonyl)-2-methylpiperazine)and the calmodulin inhibitor, W7 (NIn contrast, translation of IL- 1 (6-aminohexyl)-5-chloro1-naphthalenesulfonamine). mRNA can be enhanced by calcium ionophores and 1e~kotrienes.l~~ The regulatory role of PGE, in IL- 1 gene expression represents an important autoregulatory control mechanism, since activation of macrophages triggers IL-1 synthesis and a concomitant increase in endogenous PGE, synthesis. l4'.I4'

C. interleukin 6 Human interleukin 6, previously designated BCDF and BSF2, is synthesized as a 212amino acid precursor that is processed into a 184-amino acid secreted product.149In marked



45

contrast to TNF and IL-I,the IL-6 precursor peptide contains a hydrophobic signal sequence that spans amino acid residues - 28 to - 1. Interleukin 6 bears substantial sequence homology with granulocyte colony stimulating factor (G-CSF). Interleukin 6 and G-CSF contain four similarly positioned cysteine residues, suggesting that the two molecules may have comparable tertiary structures. Comparison of DNA sequences for IL-6 and G-CSF reveals that each gene contains five exons and four introns, and that the sizes of the corresponding introns are nearly the same. Interleuhn 6 was also previously called hybridoma plasmacytoma growth factor (HPGF), based on its ability to induce the proliferation of myeloma cells and to support hybridoma growth in cell c ~ l t u r e . ~It~should . ’ ~ be noted that IL-6 does not function as a growth-promoting factor for B lymphocytes despite its ability to augment immunoglobulin synthesis and ~ecretion.’~ Several investigators have shown that much lower concentrations of IL-6 are required to maintain hybridoma growth than to trigger B cell responses or support plasmacytoma growth. Muraguchi et al. have induced maximum growth of a BSFZdependent hybridoma line (MH60.BSFZ) with IL-6 at a concentration of 20 pg/ml. Interleukin 6-triggered B cell responses require concentrations on the order of nanograms per milliliter. Despite the capacity for human IL-6 to trigger proliferation of mouse hybridoma cells, the available amino acid sequencing data indicate that the sequences of human and murine IL-6 are different. 15‘ It is presently unknown whether discrete homologous regions of these molecules can account for the common biological activity or whether two different types of IL-6 exist. It should also be noted that despite yet another previous designation, interferon beta-2 (IFNp2), IL-6 does not have antiviral activity nor is it antigenically related to interferon beta.”-” Initial studies by Kishimoto et al. indicate that IL-6 receptors are present on activated B lymphocytes and resting T lymphocytes, but not on resting B lymphocyte^.'^^^^^^ Interleukin 6 receptors have also been identified on Epstein-Barr virus-transformed lymphoblastoid cell lines and hepatocytes, but not on Burkitt’s lymphoma cells. 76.77~149Yamasaki et al. have recently reported the cloning of a cDNA that encodes the human IL-6 receptor.’5s The IL6 receptor contains 468 amino acids, including a 90-residue domain belonging to the immunoglobulin gene superfamily and an 82-residue cytoplasmic domain that, unlike many growth factor receptors, does not contain a tyrosine kinase sequence. Two receptor populations have been identified: a high-affinity population (Kd = 1.9 x M) and a loweraffinity population (Kd = 7.3 x lo-’’ M). It has been suggested that the high-affinity receptors are the result of cooperativity resulting from dimer formation. Understanding of signal-transduction mechanisms for the IL-6 receptor is embryonic. In recent studies employing a B lymphoblastoid cell line, IL-6 induced the transcription of mRNA that encodes immunoglobulin heavy chains, yet did not trigger membrane depolarization, translocation of protein kinase C,phosphoinositol (PI) turnover, or intracellular calcium Stimulation of the same cell line with anti-surface immunoglobulin triggered PI turnover, calcium mobilization, and protein kinase C translo~ation.~~ Interleukin 6 receptor-transduction pathways have not been examined in hybridomas or plasmacytomas. Relatively little is known about IL-6 gene regulation. As noted previously, the IL-6 gene has only recently been cloned and ~ e q u e n c e d . ’Increased ~~ levels of BSF2 (IL-6) mRNA and functional IL-6 have been detected in cardiac myxoma cells and tissue extracts, res p e c t i ~ e l y . ~In~ addition, .’~~ supranormal levels of IL-6 and IL-6 mRNA have been detected in synovial tissues obtained from patients with rheumatoid arthritis. 157 Other diseases in which IL-6 dysregulation may play a role include cervical carcinoma, urothelial carcinoma, and Castleman’s disease.’49.’56 In all of these disorders, there is a propensity for the development of autoimmune manifestations that may be linked to overproduction of IL-6. It has recently been demonstrated that there are several different transcription initiation sites within the IL-6 gene. Yamasaki et al. have suggested that these different sites may be used for the expression of the IL-6 gene in different tissues. 149 It seems likely that unraveling the com-

46



plexities of IL-6 gene regulation will have important implications in understanding autoimmune disease processes.

D. Interleukin 8 Human IL-8 is a 6500-Da peptide that harbors potent chemotactic activity for neutrophils.x”90 Edman degradation analysis of the amino acid terminus, in conjunction with sequence data derived from mRNA extracted from staphylococcal enterotoxin A-stimulated mononuclear cells, suggests that IL-8 is synthesized as an arginine-lysine-rich 99-amino acid precursor protein that bears a hydrophobic signal The basic nature of IL-8 is reflected in purification strategies that have exploited its capacity to bind to silicic acid, heparin, and phosphocellulose. Microheterogeneous amino terminal variants have. been described, but these have exhibited equal activities in functional assays. Biochemical analysis of highly purified IL-8 has demonstrated that this protein is highly temperature, pH, and protease resistant.89 Peveri et al. have shown that prolonged exposure to trypsin or chymotrypsin is required to inactivate L - 8 in ~ i t r o . These * ~ investigators have also shown that exposure of IL-8 to serum does not affect its activity. This is in direct contrast to C5a, which is nearly completely inactivated by serum-derived carboxypeptidase. As noted previously, IL-8 bears significant structural homology with beta-thromboglobulin and platelet factor 4.x”90The iq vivo and in vitro biological activities of IL-8 are pleiotypic and the focus of considerable current research. Crossed desensitization studies in which IL-8 has been compared to chemotactic agents such as synthetic formyl peptide, C5a, platelet-activating factor, and leukotriene B, indicate that it acts through a specific membrane receptor.89Preliminary studies suggest that neutrophils possess as many as 20,000 receptors (Kd = 8 X lo-’’ M) per cell. Cell activation studies using human neutrophils indicate that IL-8 exposure triggers an increase in cytosolic calcium that is linked to exocytosis and the respiratory burst. These IL-8-triggered metabolic responses can be blocked with pertussis toxin, 17-hydroxywortmannin and staurosporine, which are inhibitors of GTP binding protein, the respiratory burst and exocytosis, and protein kinase C activity.158Regulation of IL-8 gene expression is the current focus of intense research activity.

IV. CYTOKINE ACTIVITIES IN INFLAMMATORY PROCESSES A. Fever Response Perusal of older nomenclature emphasizes the putative role of IL-1 in the febrile response. It has been recognized for years that the fever associated with a variety of diseases is mediated by “endogenous pyrogen” or IL-1. Interleukin 1 triggers fever by increasing prostaglandin E, (PGE,) synthesis in the anterior hypothalamic region. Because IL-1 is thought not to cross the intact blood-brain barrier, it has been suggested that IL-1 triggers PGE, synthesis by vascular endothelium in the hypothalamus. The antipyretic action of aspirin, for instance, has been demonstrated to be associated with reduced cyclooxygenase activity and a resulting decrease in PGE, synthesis. Recombinant human IL-1 alpha and IL-1 beta have both been shown to trigger this fever re~ponse.~’ At relatively low concentrations ( 1 p,g/kg), infusion of TNF triggers a rapid-onset, monophasic temperature elevation in rabbits that is indistinguishable from that induced by TL1. 159 As in the case of IL- 1, TNF-induced fever can be blocked with drugs that inhibit cyclooxygenase. Infusion of higher concentrations (10 pgkg) of TNF into rabbits results in a biphasic fever response.Is9 In this sequence, the first temperature rise is due to the direct effect of TNF and the second temperature peak is thought to be mediated by local TNFtriggered IL- 1 release. These observations reiterate the historical relationship between en-


47

dogenous pyrogen and IL- 1, and they emphasize the fundamental importance of these cytokine mediators in febrile responses that accompany many inflammatory disease states.


B. Acute-Phase Response There are fragmentary bits of in vivo and in v i m evidence that TNF, IL-1, and IL-6 all play roles in the acute-phase response. Tumor necrosis factor has been shown to stimulate the synthesis and secretion of several acute-phase proteins in human hepatoma cell lines and It appears that TNF regulates acute-phase protein synthesis isolated rat hepatocytes. and release at several levels. Mackiewicz et al. have shown that conditioned medium from lipopolysaccharide-activated monocytes influences the glycosylation of alpha- 1-proteinase inhibitor, an acute-phase protein. 163 Other investigators have provided evidence suggesting that several cytokines, including TNF, regulate the expression of acute-phase response genes.16’*161 Tumor necrosis factor has also been shown to stimulate rat liver amino acid uptake, increase hepatic responsiveness to plasma glucagon, and augment hepatic lipogenesis, events observed early in acute tissue injury or Infusion of IL-1 into experimental animals results in decreases in plasma iron and zinc concentrations in addition to an increase in the synthesis of acute-phase protein^.^' Specifically, isolated hepatocytes incubated with IL- 1 exhibit a decrease in albumin transcription and increases in the transcription of properdin factor B, metallothionen, and serum amyloid A . Interleukin 1 also augments the hepatic biosynthesis of complement protein C3, alpha1-antichymotrypsin, alpha- 1-acid glycoprotein, and inter-alpha-1-trypsin inhibitor.IM Recent studies by Gauldie et al. indicate that IL-6 (previously hepatocyte-stimulating factor) is also a major regulator of the acute-phase protein re~ponse.’~ In animal models and in several human disease states, sequential rises in serum TNF, IL-1, and IL-6 can be detected. 167,168 The precise regulatory interactions among these cytokines remain to be determined. Studies regarding the biological functions of TNF, IL-1, and IL-6 must be interpreted with caution. Exposure of some cell types to a given cytokine can lead to the secretion of different cytokines, which, in turn, are responsible for a given biological effect. Some bioassays utilized to measure cytokine activity are nonspecific. For instance, IL-6 can trigger thymocyte coproliferation, the widely used assay for IL- 1 activity. Recognition of these pitfalls, in conjunction with the availability of recombinant cytokines, has been critical to the unambiguous clarification of cytokine functions.

C. Neutrophil Activation Tumor necrosis factor, IL-1, and IL-8 play important roles in the activation of neutrophils. Tumor necrosis factor and IL-1 both enhance the adherence of neutrophils to endothelial cells through mechanisms involving the regulation of cell surface-adhesion molecules on both neutrophils and endothelial cells. Exposure of neutrophils to TNF triggers a twofold increase in the surface antigen complex designated CDw18, which is required for maximal adherence and CR3 (C3bi receptor) function. ‘69 TNF also triggers neutrophil degranulation and the respiratory burst. 170-‘72 Early studies using purified TNF suggested that it was a potent chemotactic substance, but more recent studies in which recombinant TNF has been used indicate that it is not a potent chemotaxin for neutrophil~ Tumor . ~ ~ necrosis factor has also been reported to enhance the neutrophil-mediated, antibody-dependent cellular cytotoxicity of red blood cells.173 Infusion of IL- 1 into experimental animals induces a mobilization of mature neutrophils from the bone marrow into the peripheral b l 0 0 d . I ~Interleukin ~ 1 is also thought to play a role in neutrophil accumulation into sites of acute inflammation. Several investigators have shown that IL- 1-induced neutrophil degranulation, thromboxane synthesis, and superoxide production. 175-177


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Previous nomenclature for IL-8 (neutrophil chemotactic factor, neutrophil-activating factor) provides insight into its major biological activities. As a chemotactic factor for neutrophils, IL-8 is 10 to 100 times more potent than fMLP.L58In contrast to fMLP, C5a, plateletactivating factor, and leukotriene B,, which are all chemotactic for neutrophils and monocytes, IL-8 is selectively chemotactic for neutrophils.86-90 Exposure of neutrophils to nanomolar concentrations of IL-8 results in increased cytosolic calcium coupled with shape changes, exocytosis, and a respiratory b ~ r s t . * ~Intradermal .’~~ injection of IL-8 into experimental animals is followed by an influx of neutrophils.w The precise role of IL-8 in acute inflammatory processes is a current research focus. Studies by Strieter et al. have shown that TNF and IL- 1 induce the expression and secretion of IL-8 by several cell types indigenous to the These studies suggest the possibility that IL-8 may function as a “distal mediator” of the acute inflammatory process. One can envision a scenario in which TNF andlor IL-1 elaboration leads to the secretion of IL-8, which, in turn, attracts and activates neutrophils.

D. Effects on Endothelium The vascular endothelium actively participates in coagulation and inflammatory responses. Studies by several groups of investigators have shown that TNF and IL-1 regulate a variety of endothelial cell activities through mechanisms involving the modulation of cell surface molecules. Tumor necrosis factor and IL-1 induce a series of changes in the endothelium that favor thrombosis. In vitro studies have shown that TNF and IL-1 act through similar mechanisms to induce tissue factor-like procoagulant activity in cultured human endothelial cells. 179.180 TNF also suppresses endothelial cell cofactor activity for the anticoagulant protein C pathway.181Finally, treatment of cultured human endothelial cells with IL-1 induces the synthesis of plasminogen activator inhibitor, thus further favoring thrombosis. By virtue of a possible association with states of disseminated intravascular coagulation, these procoagulant activities may have particular relevance to inflammatory states that accompany sepsis. Tumor necrosis factor and IL-1 also appear to play pivotal roles in leukocyte-endothelial adhesion. As noted previously, TNF and IL-1 act on neutrophils, rendering them more “sticky” than normal. Through separate sets of mechanisms, TNF and IL-1 also act on endothelial cells, rendering them more adhesive for neutrophils, monocytes, and lymphocytes. 183-185 Clearly, enhancement of endothelial adhesivity is a critical step in inflammatory cell recruitment in acute and chronic inflammatory states as well as in some immunologic processes. Biochemical and immunohistochemical studies using cultured endothelial cells and human tissue biopsies, respectively, suggest that expression of adhesion molecules by endothelial cells are an important functional correlate of “endothelial activation”. Surgical pathologists have recognized the morphologic hallmarks of activated endothelium for a number of years. These morphologic changes include increased cell volume, cytoplasmic basophilia, and prominence of nucleoli, changes often associated with metabolic activation and increased protein synthetic capacity. It has become clear that TNF and LL-1 induce the expression of endothelial leukocyte adhesion molecule (ELAM)-1, which is not expressed on unstimulated endothelial cells, as well as intracellular adhesion molecule (1CAM)-1, which is present on unstimulated endothelial cells but can be upregulated. 186*187 Studies employing specific blocking monoclonal antibodies indicate that cytokine-induced ELAM-1 expression is transient, peaks at 4 to 6 h after exposure, and is responsible for neutrophil binding. ICAM- 1 mediates lymphocyte (and possibly monocyte and neutrophil) adhesion. The expression of ICAM-1 is more stable, lasting for greater than 24 h. The ligand for ELAM-1 is currently being defined, while the ligand for ICAM-1 appears to be LFA-1 (CDllaCD18), and perhaps Mac1 (CDllb CD18) and gp150 (CDllc CD18).L8s,’88 Tumor necrosis factor and IL-1 also increase endothelial cell PGI, synthetic capacity,



49

platelet-activating factor synthesis, IL- 1 secretion, and colony-stimulating factor secretion.30.31.’89-’91 All of these activities may potentially contribute to acute inflammatory states. While perhaps not directly relevant to acute inflammation, TNF and IL-1 can stimulate angiogenesis and growth factor ~ e c r e t i o n . ~Tumor ~ . ~ ’ necrosis factor, but not IL-1, induces increased expression of class I major histocompatibility antigens by endothelial cells. 19* The advances in our understanding of “endothelial activation” probably represent the most eloquent example to date of the role of cytokines as “information bearers” in the coordination of the acute inflammatory response.

E. Miscellaneous in addition to their direct roles in the acute inflammatory response, TNF and IL-1 exhibit other activities that appear to be important in inflammation-associated conditions. For instance, TNF and IL-I have been shown to stimulate bone and cartilage r e s o ~ p t i o nRecently, .~~ human osteoclast-activating factor was purified and found to be identical to IL- 1 beta. 193 Low concentrations of TNF and IL-1 can stimulate the release of calcium from fetal long bones maintained in c ~ l t u r e . ‘ ~Under ~ . ’ ~ similar ~ conditions, TNF and IL-1 inhibit bone collagen synthesis and osteoblast alkaline phosphatase activity. l9’-I9’ While these cytokine activities seem to have particular relevance to malignant osteolysis, normal bone remodeling, and age-related bone loss, they may also be important in the bony erosion that accompanies inflammatory joint diseases such as rheumatoid arthritis. Tumor necrosis factor and IL-1 also trigger degradation of chondroitin sulfate-rich proteoglycan matrix materials within cartilage.’95-’97Secretion of proteolytic enzymes is known to be important in the damage and remodeling of connective tissues in inflammatory reactions. Tumor necrosis factor and IL-I have been shown to stimulate collagenase and PGE, production by isolated synovial cells and dermal fibroblasts. ‘98-202 These examples further emphasize the pleiotropic proinflammatory activities of TNF and IL-1. Interleukin 6 exhibits a much narrower range of proinflammatory activities than TNF or IL-1 .53 It should be reemphasized that IL-6 synthesis can be induced in several cell types by TNF or IL-1. In addition to its role in the fever response and the acute-phase response, IL-6 has been shown in v i m to trigger Gohematopoietic cells into an interleukm 3-responsive phase.53 Of course, IL-6-mediated B cell proliferation and antibody secretion ultimately have relevance to immune antibody-mediated inflammatory reactions. Although IL-8 has not yet been exhaustively studied, early studies suggest that it has the most circumscribed set of acute proinflammatory activities of these cytokines. The chief role of IL-8 in acute inflammation appears to be neutrophil chemotaxis and activation.

V. CONCLUSIONS In the last 10 to 15 years, modem biochemical and immunological techniques have led to a much more detailed understanding of the events that regulate the acute inflammatory response. Our current understanding of the role of “inflammatory cytokines” in acute inflammation suggests that TNF, IL-I , and IL-6 all play roles in the fever response and the acute-phase response (Figure 1). Tumor necrosis factor and IL-1 are important mediators of ‘‘endothelial activation”, a complex response that is important in trafficking neutrophils and other inflammatory cells into a site of insult. Interleukin 6 is also an important mediator of the humoral immune response. The most recently described cytokine, IL-8, appears to be an important and selective chemotactic factor for neutrophils. The large number of proinflammatory mediators and their multifaceted activities emphasize the complexity of the acute inflammatory response.

50

Critical Reviews in Clinical Laboratory Sciences Hypothalmus > I

-

A


Liver

I

L//

Fever response

Termlnal B cell dlfferentletlon

I

Acute phase response

I

,

i

Humorel Immune Response

INSULT

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FIGURE 1. Tumor necrosis factor and interleukins I , 6, and 8 play major regulatory roles in the acute inflammatory response.

ACKNOWLEDGMENTS I would like to sincerely thank Kimberly Drake and Jennie Fricke for manuscript preparation and Robin Kunkel for the art work.

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