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IL6 and the acute phase reaction
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6
755
IL6 and the acute phase reaction J. Gauldie
(I), C. Richards
tl) and H. Baumann
t2)
(I) Department of Pathology, McMaster University, Hamilton, Ontario (Canada) L8N 325, and (‘) Department of Molecular and Cell Biology, Roswell Park Cancer Institute, Buffalo, NY (USA) 14263
After tissue injury, trauma or infection, the body initiates a complex series of reactions aimed at stopping further damage, ridding the organism of infectious agents and initiating repair mechanisms to return the tissue to normal function. This normal homeostatic response is called inflammation and involves both local as well as systemic changes. When the response assumes a chronic nature or there is an overwhelming initiation, the outcome is more pathologic, with tissue damage and loss of function. Local changes include increased vascular permeability and pain with tissue swelling and redness, mediated primarily by vasoactive and lipid-derived factors, while the systemic reaction, the acute phase reaction, involves fever, leukocytosis, plasma cortisol changes and the hepatic response resulting in increased plasma levels of acute phase proteins. This hepatic response is a highly protective one, being non-specific and rapid, involving the release of antiproteases and opsonins, and has been maintained in a similar fashion throughout phylogeny (Gauldie, 1991; Fey and Gauldie, 1990; Koj, 1985; Kushner, 1982). Given that the tissue involved in many cases is distant from the liver, yet the hepatocyte responds to tissue trauma by increased synthesis and secretion of acute phase proteins, the presence of tissue-derived bloodborne factors which target hepatocytes, as suggested by Koj (1974) is realistic. Indeed, the factor(s) that initiate this response should be seen as a protective homeostatic factor(s), one that controls the inflammatory response. This was the state of thought as I became interested in molecular events in the acute phase response and initiated the quest for the hepatic regulatory factor. I believed that since most of the known functions of acute phase proteins are anti-proteases or opsonins, the factor that initiates their synthesis would be a crucial antiinflammatory mediator (Gauldie and Baumann, 1991). However, since most events of inflammation precede the development of immunity, there would likely be overlap in the roles played by such factor(s), and regulating both inflammation and immunity would have obvious therapeutic potential.
In the mid 1980’s I began to collaborate with two individuals who had a major impact on the work. Alex Koj, for many years invoived in acute phase protein studies, spent a sabbatical with me in 1984/85 and Heinz Baumann, interested in liver cell gene regulation, was only an hour’s drive away in Buffalo. Together we developed suitable in vitro cultures of primary rat hepatocytes and rat and human hepatoma cells along with a number of acute phase protein antisera to measure the products of stimulated hepatocytes (Koj et al., 1984; Baumann et al., 1987a,b; Baumann, 1989). At the same time, two other groups were working on hepatocyte cultures. Jerry Fuller and his group were the first to describe a factor derived from monocytes, called hepatocyte stimulating factor (HSF), which stimulated synthesis of fibrinogen in rat hepatocytes (Ritchie and Fuller, 1983). Peter Heinrich, meanwhile, was searching for a factor, also from monocytes, which caused rat hepatocytes to synthesize aZmacroglobulin, an acute phase protein in the rat (Bauer et al., 1984; Heinrich et al., 1990). While it was obvious that cloned and purified IL1 and/or TNF could elicit the full hepatic acute phase response in vivo (including fibrinogen), no one could confirm such a fact with in vitro cultures and thus we felt that IL1 or TNF could not be the factors directly responsible for the acute phase response. In early 1987, with Carl Richards, a graduate student at that time, we used an antiserum obtained from Pravin Sehgal and recombinant material from Toshio Hirano and Tadimutso Kishimoto to show that the factor that was able to initiate the full hepatic acute phase response, both in vitro and in vivo, was interferon P2/BSF-2/IL6 (Gauldie et al., 1987). These findings were first reported in May 1987 at a Cold Spring Harbour meeting on liver cell gene regulation and were quickly confirmed by Heinrich and others (Andus et al., 1987 ; Morrone et al., 1988 ; Darlington et al., 1989). Indeed, IL6 was shown to be active at very low concentrations both in vitro and in vivo (Marinkovic et al., 1989; Geiger et al., 1988), and could be detected bound to the surface of hepatocytes after injection or exposure (Heinrich et al.,
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1990; Sonne et al., 1990) associated with an 80-kDa cell receptor (Yamasaki et a/., 1988). IL6 exposure initiates nuclear protein interaction (including members of C/EBP family) with specific sequences of the regulatory region of acute phase protein genes (Prowse and Baumann, 1988; Poli and Cortese, 1989; Baumann et al., 1990; Hattori et al., 1990; Majello et al., 1990; Won and Baumann, 1990), and acts synergistically with corticosteroid to initiate gene transcription (Baumann and Maquat, 1986; Prowse and Baumann, 1990; Fey et al., 1989). The fact that IL6 is also active in modulation of the immune response is not surprising, given our expectations. Using a series of hepatoma lines (in particular, a rat line H35) and primary hepatocytes, Baumann and I showed that the expression of most, if not all, acute phase protein genes was regulated by IL6, particularly in the presence of corticosteroid, and that a subclass of the genes (type 1 proteins) was additionally regulated by ILl/TNF (Baumann et al., 1987a, b ; Baumann and Gauldie, 1990 ; Gauldie and Baumann, 1991). This classification has recently been extended to include CRP, the archetypal human acute phase protein (Ganapathi et al., 1988 ; Depraetere et al., 1991). We found evidence of synergistic stimulation between the cytokines, as seen with al acid glycoprotein, and inhibition of IL6 stimulation by ILl, as seen with fibrinogen. Thus, varying levels, exposure sequence and/or mixtures of cytokines could result in different serum levels of acute phase proteins. Moreover, since IL1 induces IL6 in stromal cells, this indirect effect seems the likely mechanism for IL1 stimulation of fibrinogen in vivo. As is the case for a number of cytokines, there are other mediators that similarly regulate the hepatic acute phase response. Baumann showed that IL11 and leukemia inhibitory factor (LIF) act similarly in the liver as does IL6 (Baumann and Wong, 1989; Baumann and Schendel, 1991) and Richards showed that oncostatin M (OM) exhibits similar hepatocyte stimulation (Richards et al., 1992). The fact that four different cytokines, operating through four different ligand binding receptors on the hepatocyte, regulate the exact same set of genes and demonstrate similar synergy with IL1 and corticosteroid, suggests a common signal for gene regulation. Moreover, the cytokines initiate nuclear protein interaction with the same regulatory region(s) of the acute phase protein genes (Richards et al., 1992). Such coalescence of signal transduction suggests common intermediates and this has been supported by the recent identification of the second component of the LIF ligand-binding receptor as being identical to the molecule (gp 130) used by the IL6 ligand binding receptor (Taga et al., 1989; Hibi et al., 1990; Gearing et al., 1992). Mechanisms of IL6-mediated signal transduction in the hepatocyte are unclear but may involve GTP binding (Richards et al., 1991).
IN IiWA4UNOLOGY Other aspects of the acute phase response are also mediated in part by IL6. Like ILI, IL6 can induce a febrile response mediated by the production of prostaglandin (Rothwell et al., 1991 ; Dinarello et al., 1991). In addition, in vitro and in vivo, IL6 can induce the release of CRF, ACTH and subsequently corticosteroid by the pituitary/adrenal axis (Woloski et al., 1985; Naitoh et al., 1988). Whether any of the other three cytokines also act in this manner is not known. While the IL6-like hepatocyte-stimulating activity of the other cytokines is acknowledged, there is little data to implicate them in induction of the acute phase in vivo, and IL6 is likely the major regulator of this response. Specific antisera to IL6 can inhibit > 95 070 of the hepatocyte-stimulating activity of either LPS-stimulated monocyte- or IL 1/TNFstimulated fibroblast-conditioned medium. After trauma or infection, raised IL6 serum levels are easily detected, coincident with the onset of acute phase protein synthesis (Nijsten et al., 1987; Houssiau et al., 1988; Ohzato et al., 1992; Gauldie et al., 1990; Jablons et al., 1989). Overexpression of IL6 in transgenie systems results in the hepatic acute phase response (Akira et al., 1990; Hirano, 1992), and direct anti-inflammatory activity of IL6 is supported by recent data showing inhibition of the development of experimental arthritis in the rat (Mihara et al., 1991). The antiinflammatory aspect of IL6 action can be extended to local tissue protection as it regulates specific expression of tissue inhibitor of metalloproteinase (TIMP) in fibroblasts (Richards et al., submitted). However, attempts to block the acute phase induction activity of IL6 in experimental inflammation using inhibitory poly- and/or monoclonal antibodies have met with limited success. Complexed IL6 apparently extends the normal rapid plasma half-life of the native mediator (T’/, of 7 to 15 min) and thus may variably contribute to enhanced plasma IL6 activity when diminished levels are expected. This may explain the counterfinding of an inflammatory role for IL6 as reported for lethal E. coli infection in mice (Starnes et al., 1990). There are varying reports of the regulation of the IL6 receptor on hepatocytes in vitro (Bauer et al., 1989; Baumann et al., 1990; Rose-John et al., 1990; Schooltink et al., 1991). In vI’vo, IL6 administration to rats elicits a rapid and marked upregulation of the mRNA for the 80-kDa receptor in the liver, implying an enhancement of the response of the liver at a time when rapid deployment of the antiinflammatory acute phase proteins is most needed. Serum levels of IL6 decrease to normal 24-36 h after trauma and are accompanied by a return to normal levels of expression of hepatic IL6 receptor and normal serum levels of the acute phase proteins. Taken together, these data support the major antiinflammatory role played by IL6 in the induction
INTERLEUKIN of the very important and protective acute phase response. Whether IL6 is the only regulator in all situations, or how much is contributed by other cytokines, remains to be established. However, we suggest that administration of IL6 or induction of IL6 is an antiinflammatory approach, leading to protection against further tissue destruction and returning homeostatic balance to the system.
References Akira, S., Hirano, T., Taga, T. & Kishimoto, T. (1990), Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF). FASEB J., 4, 2860-2867. Andus, T., Geiger, T., Hirano, T., Northoff, H., Ganter, U., Bauer, J., Kishimoto,T. & Heinrich, P.C. (1987), Recombinant human B cell stimulatory factor 2 (BSF-Z/IFN-beta2) regulatesbeta-fibrinogenand albuminmRNA levelsin Fao-9cells. FEBS Letters, 221, 18-22. Bauer, J., Bauer, T.M., Kalb, T., Taga, T., Lengyel, G., Hirano, T., Kishimoto, T., Acs, G., Mayer, L. & Gerok, W. (1989),Regulationof interleukin 6 receptor expressionin human monocytesand monocytederived macrophages.Comparisonwith the expression in human hepatocytes. J. exp. Med., 170, 1537-1549. Bauer, J., Birmelin, M., Northoff, G.H., Northemann, W., Tran-Thi, T.A., Ueberberg, H., Decker, K. & Heinrich, P.C. (1984), Induction of rat alpha-2-macroglobulinin vivo and in hepatocyte primary cultures: synergisticaction of glucocorticoids and a Kupffer cell derived factor. FEBS Letters, 177, 89-94. Baumann, H. (1989), Hepatic acute phase reaction in vivo and in vitro. In vitro Cell. Dev. Biol., 25, 115-126. Baumann,H. & Gauldie, J. (1990), Regulationof hepatic acute phase plasma protein genesby hepatocyte stimulatingfactors and other mediatorsof inflammation. Mol. biol. Med., 7, 147-159. Baumann, H. & Maquat, L.E. (1986), Localization of DNA sequences involved in dexamethasonedependentexpressionof the rat al-acid-glycoprotein gene. Mol. cell. Biol., 6, 2551-2561. Baumann,H., Morella, K.K., Jahreis,G.P. & Marinkovic, S. (1990),Distinct regulation of the interleukin-1 and interleukind response elementsof the rat haptoglobin gene in rat and human hepatomacells. Mol. cell. Biol., 10, 5967-5976. Baumann, H., Onorato, V., Gauldie, J. & Jahreis,G.P. (1987a),Distinct setsof acutephaseplasmaproteins are stimulatedby separatehepatocytestimulatingfactors and monokinesin rat hepatomacells. J. biol. Chem.,
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Baumann,H., Richards,C. & Gauldie, J. (1987b), Interactions among hepatocyte stimulating factors, interleukin-1, and glucocorticoids for regulation of acute phase plasmaproteins in human hepatoma (HepG2) cells. J. Immunol., 139, 4122-4128.
6 Baumann,H. & Schendel,P. (1991), Interleukin-11 regulatesthe hepaticexpressionof the sameplasmaprotein genesas interleukin-6. J. biol. Chem.. 266, 20424-20427. Baumann, H. & Wong, G.G. (1989), Hepatocytestimulating factor III sharesstructural and function identity with leukemiainhibitory factor. J. Immunol., 143, 1163-1167. Baumann,M., Baumann,H. & Fey, G.H. (1990),Molecular cloning, characterization and functional expression of the rat liver interleukin-6 receptor. J. biol. Chem., 265, 19853-19862. Darlington, G.J., Wilson, D.R., Revel, M. & Kelly, J.H. (1989),Responseof liver genesto acute phasemediators. Ann. N.Y. Acad. Sci., 557, 310-316. Depraetere,S., Willems, J. & Joneau, M. (1991),Stimulation of CRP secretionin HepG2 cells: cooperative effect of dexamethasoneand interleukin-6. Agents Actions,
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Dinarello, C.A., Cannon, J.G., Mancilla, J., Bishai, I., Lees,J. & Coceani,F. (1991),Interleukin-6 asan endogenouspyrogen: induction of prostaglandinE2 in brain but not in peripheralblood mononuclearcells. Brain Res., 562, 199-206. Fey, G.H. & Gauldie, J. (1990),The acutephaseresponse of the liver in inflammation, in “Progressin liver diseases, Vol. 9” (H. Popper and F. Schaffner) (pp. 89-116). W.B. Saunders,Philadelphia. Fey, G.H., Hattori, M., Northernann,W., Abraham, L.J., Baumann,M., Braciak, T.A., Fletcher, R.G., GauIdie, J., Lee, F. & Reymond, M.F. (1989), Regulation of rat liver acute phasegenesby interleukin-6 and production of hepatocyte stimulating factors by rat hepatomacells. Ann. iV. Y. Acad. Sci., 557, 317-331. Ganapathi, M.K., May, L.T., Schultz, D., Brabenec,A., Weinstein,J., Sehgal,P.B. & Kushner,I. (1988),Role of interleukin-6 in regulatingsynthesisof C-reactive protein and serumamyloid A in human hepatoma cell lines. Biochem. biophys. Res. Commun., 157, 271-277. Gauldie, J. (1991),Acute phaseresponse,in “Encyclopedia of human biology, Vol. 1” (R. Dulbecco) (pp. 25-35). Academic Press,New York, London. Gauldie, J. & Baumann, H. (1991), Cytokines and acute phaseprotein expression,in “Cytokines and inflammation” (E.S. Kimball) (pp. 275-305).CRC Press, Boca Raton, FL. Gauldie, J., Northernann, W. & Fey, G.H. (1990), IL-6 functions asan exocrine hormonein inflammation : hepatocytes undergoing acute phase responses require exogenousIL-6. J. Immunol., 144, 38043808. Gauldie, J., Richards, C., Harnish, D., Lansdorp, P. & Baumann,H. (1987),Interferon 82/B-cellstimulatory factor type 2 sharesidentity with monocyte-derived hepatocyte-stimulatingfactor andregulatesthe major acute-phase protein responsein liver cells.Proc. natl. Acad. Sci. (Wash.), 84, 7251-7255. Gearing, D.P., Comeau, M.R., Friend, D.J., Gimpel, S.D., Thut, C. J., McGourty, J., Brasher,K.K., King, J.A., Gillis, S., Mosley, B., Ziegler, S. & Cosman, D. (1992),The IL-6 signaltransducer,gp130: an oncostatinM receptorand affinity converter for the LIF receptor. Science, 255, 1434-1437.
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Geiger, T., Andus, T., Klapproth, J., Hirano, T., Kishimoto, T. & Heinrich, P.C. (1988), Induction of rat acutephase proteins by interleukin-6 in vivo. Europ. J. Immunol., 18, 711-721. Hattori, M., Abraham, L.J., Northernann, W. & Fey, G.H. (1990), Acute-phase reaction induces a specific complex between hepatic nuclear proteins and the interleukin-6 response element of the rat aZmacroglobulin gene. Proc. null. Acad. Sci. (Wash.), 87, 2364-2368. Heinrich, P.C., Castell, J.V. & Andus, T. (1990), Interleukind and the acute phase response. Biochem. J., 265, 621-636. Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T. & Kishimoto, T. (1990), Molecular cloning and expression of an IL-6 signal transducer, gpl30. Cell, 63, 1149-1157. Hirano, T. (1992), IL-6 and its relation to inflammation and disease. Clin. Immunol. Immunopath., 62, S60-S65. Houssiau, F., Devogelaer, J.-P., Van Damme, J., Nagant de Deuxchaisnes, C. & Van Snick, J. (1988), Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritises. Arthritis Rheum., 3 1, 184-788. Jablons, D.M., Mule, J.J., McIntosh, J.K., Sehgal, P.B., May, L.T., Huang, C.M., Rosenberg, S.A. & Lotze, M.T. (1989), IL-6/1FN-P-2 as a circulating hormone. Induction by cytokine administration in humans. J. Immunol., 142, 1542-1547. Koj, A. (1974), Acute-phase reactants - their synthesis, turnover and biological significance, in “Structure and function of plasma proteins” (A.C. Allison) (p. 73). Plenum Press, London. Koj, A. (1985), Acute-phase reactants - their synthesis turnover and biological significance, in “Injury and infection” (A.H. Gordon and A. Koj) (pp. 145-160). Elsevier, Amsterdam. Koj, A., Gauldie, J., Regoeczi, E., Sauder, D.N. & Sweeney, G.D. (1984), The acute-phase response of cultured rat hepatocytes. System characterization and the effect of human cytokines. Biochem. J., 224, 505-514. Kushner, I. (1982), The phenomenon of the acute phaSe response. Ann. N. Y. Acad. Sci., 389, 39-48. Majello, B., Arcone, R., Toniatti, C. & Ciliberto, G. (1990), Constitutive and IL&induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J., 9, 457-465. Marinkovic, S., Jahreis, G.P., Wong, G.G. & Baumann, H. (1989), IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J. Immunol., 142, 808-812. Mihara, M., Ikuta, M., Koishihara, Y. & Ohsugi, Y. (1991), IL-6 inhibits delayed-type hypersensitivity and the development of adjuvant arthritis. Europ. J. Immunol., 21, 2327-2331. Morrone, G., Ciliberto, G., Oliviero, S., Arcones, R., Dente, L., Content, J. & Cortese, R. (1988), Recombinant interleukin-6 regulates the transcriptional activation of a set of human acute phase genes. J. biol. Chem., 263, 12554-12558. Naitoh, Y., Fukata, J., Tominaga, T., Nakai, Y., Tamai, S., Mori, K. & Imura, H. (1988), Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in
conscious, freely moving rats. Biochem. biophys. Res. Commun., 155, 1459-1463. Nijsten, M. W .N., de Groot, E.R., ten Duis, H. J., Hack, C.E. & Aarden, L.A. (1987), Serum levels of interleukin-6 an acute phase responses. Lancet, II, Letter : 921. Ohzato, H., Yoshizaki, K., Nishimoto, N., Ogata, A., Tagoh, H., Monden, M., Gotoh, M., Kishimoto, T. & Mori, T. (1992), Interleukin-6 as a new indicator of inflammatory status : detection of serum levels of interleukind and C-reactive protein after surgery. Surgery, 111, 201-209. Poli, V. & Cortese, R. (1989), Interleukin-6 induces a liverspecific nuclear protein that binds to the promoter of acute-phase genes. Proc. natl. Acad. Sci. (Wash.), 86, 8202-8206. Prowse, K.R. & Baumann, H. (1988), Hepatocytestimulating factor, P2-interferon, and interleukin-1 enhance ellpression of the rat al-acid glycoprotein gene via a distal upstream regulatory region. Mol. ceil. Biol., 8, 42-51. Prowse, K.R. & Baumann, H. (1990), Molecular characterization and acute-phase expression of the multiple Mus caroli al-acid glycoprotein (AGP) genes. J. biol. Chem., 265, 10201-10209. Richards, C., Brown, T.J., Shoyab, M., Baumann, H. & Gauldie, J. (1992), Recombinant oncostatin M stimulates the production of acute-phase proteins in HepG2 cells and rat primary hepatocytes in vitro. J. Immunol., 148, 1731-1736. Richards, C., Gauldie, J. & Baumann, H. (1991), Cytokine control of acute-phase protein expression. Europ. Cytokine Net., 2, 89-98. Ritchie, D.G. & Fuller, G.M. (1983), Hepatocytestimulating factor: a monocyte-derived acute-phase regulatory protein. Ann. N. Y. Acad. Sci., 408, 490-502. Rose-John, S., Schooltink, H., Lenz, D., Hipp, E., Dufhues, G., Schmitz, H., Schiel, X., Hirano, T., Kishimoto, K. & Heinrich, P.C. (1990), Studies on the structure and regulation of the human hepatic interleukind receptor. Europ. J. Biochem., 190, 19-83. Rothwell, N.J., Busbridge, N.J., LeFeuvre, R.A., Hardwick, A.J., Gauldie, J. & Hopkins, S.J. (1991), Interleukin-6 is a centrally acting endogenous pyrogen in the rat. Canad. J. Physiol. Pharmacol., 69, 1465-1469. Schooltink, H., Stoyan, T., Lenz, D., Schmitz, H., Hirano, T., Kishimoto, T., Heinrich, P.C. & Rose-John, S. (1991), Structural and functional studies on the human hepatic interleukind receptor. Biochem. J., 277, 659-664. Sonne, O., Davidson, O., Moller, B.K. & Munck, P.C. (1990), Cellular targets and receptors for IL-6. - I. In vivo and in vitro uptake of IL-6 in liver and hepatocytes. Europ. J. clin. Invest., 20, 366-376. Starnes, H.F., Pearce, M.K., Tewari, A., Yim, J.H., Zou, J. & Abrams, J.S. (1990), Anti-IL-6 monoclonal antibodies protect against lethal E. coli infection and lethal tumor necrosis factor-a challenge in mice. J. Immunol., 145, 4185-4191. Taga, T., Hibi, M., Hirata, Y., Yamasaki, K., Yasukawa, K., Matsuda, T., Hirano, T. & Kishimoto, T.
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(1989), Interleukin-6 (IL-6) triggers the association of its receptor (IL-6-R) with a possible signal transducer, gp 130. Cell, 58, 573-581. Woloski, B.M.R.N.J., Smith, E.M., Meyer, W.J. III, Fuller, G.M. & Blalock, J.E. (1985), Corticotropinreleasing activity of monokines. Science, 230, 1035-1037. Won, K.-A. & Baumann, H. (1990), The cytokine response
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element of the rat al-acid glycoprotein gene is a complex of several interacting regulatory sequences.Mol. cell. Biol., 10, 3965-3978. Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B., Taniguchi, T., Hirano, T. KcKishimoto, T. (1988), Cloning and expression of the human interleukin-6 (BSF-2/IFNP2) receptor. Science, 241. 825-828.
6 and autoimmunity
and plasma cell neoplasias
T. Hirano Division
of Molecular Oncology, Biomedical Research Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka 565 (Japan)
1. Involvement of IL6 in B-cell abnormalities chronic inflammation
in
It has been implied that chronic inflammation may induce B-cell growth and differentiation, leading to the facilitating of autoimmune disease and B-cell malignancies. Patients with pre-existing chronic inflammations show polyclonal hypergammaglobulinaemia and frequently develop plasma cell neoplasias or lymphoma (Isobe and Osserman, 197 1; Isomaki et al., 1978; Shoenfeld and Isenberg, 1988; Rook and Stanford, 1992). In animal models, mineral oil or pristane that induces chronic inflammation can elicit not only autoimmune rheumatoid arthritis, but also plasmacytoma in certain strains of mice (Potter and Boyce, 1962; Potter and Wax, 1981). Infiltration of polyclonal plasmacytosis was initially observed in the pristane-induced granulomatous tissue, and subsequently plasmacytoma, generated exclusively in the inflammatory lesion. The evidence strongly suggested the role of inflammatory cells in polyclonal plasmacytosis and the generation of plasma cell neoplasias, although the mechanisms had not been well documented until the molecular cloning of interleukin 6 (IL6). IL6 is a multifunctional cytokine involved in immune response, inflammation and haematopoiesis, which is a growth- and/or differentiation-inducing factor (Sehgal et al., 1989; Hirano and Kishimoto, 1990; Van Snick, 1990). In relation to the role of inflammatory cells in the pathogenesis of polyclonal
Center,
B-cell abnormalities and malignancies, IL6 was identified as a factor produced by virus-infected cells (Weissenbach et al., 1980) or inflammatory cells infiltrated in pleural effusion of patients with pulmonary tuberculosis (TB) (Teranishi et al., 1982) and an inflammatory cytokine, ILl, an inducible 26-kDa protein (Haegeman et al., 1986). Furthermore, B-cell differentiation factor (Hirano et al., 1985, 1986) and plasmacytoma/hybridoma/myeloma growth factor (Van Damme et al., 1987; Van Snick et al., 1988; Aarden et al., 1985; Nordan and Potter, 1986; Kawano et al., 1988), both of which had been independently investigated, turned out to be an identical molecule, IL6. In addition, hepatocytestimulating factor which regulates the biosynthesis of a variety of acute phase proteins was also found to be identical with IL6 (Gauldie et al., 1987). These facts indicate that one molecule, IL6, which is produced by inflammatory cells such as antigenactivated lymphocytes and/or macrophages, virusinfected fibroblast, and/or lymphocytes and pristanestimulated macrophages, is a real molecule governing both the immune response leading to B-cell growth and differentiation into plasma cells and the acute-phase reaction. The other critical finding relevant to the involvement of IL6 in B-cell abnormalities was obtained in patients with cardiac myxoma who showed a variety of autoimmune symptoms, such as hypergammaglobulinaemia, the presence of autoantibodies and an increase in acute phase proteins, all of which disappeared after the resection of
6
755
IL6 and the acute phase reaction J. Gauldie
(I), C. Richards
tl) and H. Baumann
t2)
(I) Department of Pathology, McMaster University, Hamilton, Ontario (Canada) L8N 325, and (‘) Department of Molecular and Cell Biology, Roswell Park Cancer Institute, Buffalo, NY (USA) 14263
After tissue injury, trauma or infection, the body initiates a complex series of reactions aimed at stopping further damage, ridding the organism of infectious agents and initiating repair mechanisms to return the tissue to normal function. This normal homeostatic response is called inflammation and involves both local as well as systemic changes. When the response assumes a chronic nature or there is an overwhelming initiation, the outcome is more pathologic, with tissue damage and loss of function. Local changes include increased vascular permeability and pain with tissue swelling and redness, mediated primarily by vasoactive and lipid-derived factors, while the systemic reaction, the acute phase reaction, involves fever, leukocytosis, plasma cortisol changes and the hepatic response resulting in increased plasma levels of acute phase proteins. This hepatic response is a highly protective one, being non-specific and rapid, involving the release of antiproteases and opsonins, and has been maintained in a similar fashion throughout phylogeny (Gauldie, 1991; Fey and Gauldie, 1990; Koj, 1985; Kushner, 1982). Given that the tissue involved in many cases is distant from the liver, yet the hepatocyte responds to tissue trauma by increased synthesis and secretion of acute phase proteins, the presence of tissue-derived bloodborne factors which target hepatocytes, as suggested by Koj (1974) is realistic. Indeed, the factor(s) that initiate this response should be seen as a protective homeostatic factor(s), one that controls the inflammatory response. This was the state of thought as I became interested in molecular events in the acute phase response and initiated the quest for the hepatic regulatory factor. I believed that since most of the known functions of acute phase proteins are anti-proteases or opsonins, the factor that initiates their synthesis would be a crucial antiinflammatory mediator (Gauldie and Baumann, 1991). However, since most events of inflammation precede the development of immunity, there would likely be overlap in the roles played by such factor(s), and regulating both inflammation and immunity would have obvious therapeutic potential.
In the mid 1980’s I began to collaborate with two individuals who had a major impact on the work. Alex Koj, for many years invoived in acute phase protein studies, spent a sabbatical with me in 1984/85 and Heinz Baumann, interested in liver cell gene regulation, was only an hour’s drive away in Buffalo. Together we developed suitable in vitro cultures of primary rat hepatocytes and rat and human hepatoma cells along with a number of acute phase protein antisera to measure the products of stimulated hepatocytes (Koj et al., 1984; Baumann et al., 1987a,b; Baumann, 1989). At the same time, two other groups were working on hepatocyte cultures. Jerry Fuller and his group were the first to describe a factor derived from monocytes, called hepatocyte stimulating factor (HSF), which stimulated synthesis of fibrinogen in rat hepatocytes (Ritchie and Fuller, 1983). Peter Heinrich, meanwhile, was searching for a factor, also from monocytes, which caused rat hepatocytes to synthesize aZmacroglobulin, an acute phase protein in the rat (Bauer et al., 1984; Heinrich et al., 1990). While it was obvious that cloned and purified IL1 and/or TNF could elicit the full hepatic acute phase response in vivo (including fibrinogen), no one could confirm such a fact with in vitro cultures and thus we felt that IL1 or TNF could not be the factors directly responsible for the acute phase response. In early 1987, with Carl Richards, a graduate student at that time, we used an antiserum obtained from Pravin Sehgal and recombinant material from Toshio Hirano and Tadimutso Kishimoto to show that the factor that was able to initiate the full hepatic acute phase response, both in vitro and in vivo, was interferon P2/BSF-2/IL6 (Gauldie et al., 1987). These findings were first reported in May 1987 at a Cold Spring Harbour meeting on liver cell gene regulation and were quickly confirmed by Heinrich and others (Andus et al., 1987 ; Morrone et al., 1988 ; Darlington et al., 1989). Indeed, IL6 was shown to be active at very low concentrations both in vitro and in vivo (Marinkovic et al., 1989; Geiger et al., 1988), and could be detected bound to the surface of hepatocytes after injection or exposure (Heinrich et al.,
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1990; Sonne et al., 1990) associated with an 80-kDa cell receptor (Yamasaki et a/., 1988). IL6 exposure initiates nuclear protein interaction (including members of C/EBP family) with specific sequences of the regulatory region of acute phase protein genes (Prowse and Baumann, 1988; Poli and Cortese, 1989; Baumann et al., 1990; Hattori et al., 1990; Majello et al., 1990; Won and Baumann, 1990), and acts synergistically with corticosteroid to initiate gene transcription (Baumann and Maquat, 1986; Prowse and Baumann, 1990; Fey et al., 1989). The fact that IL6 is also active in modulation of the immune response is not surprising, given our expectations. Using a series of hepatoma lines (in particular, a rat line H35) and primary hepatocytes, Baumann and I showed that the expression of most, if not all, acute phase protein genes was regulated by IL6, particularly in the presence of corticosteroid, and that a subclass of the genes (type 1 proteins) was additionally regulated by ILl/TNF (Baumann et al., 1987a, b ; Baumann and Gauldie, 1990 ; Gauldie and Baumann, 1991). This classification has recently been extended to include CRP, the archetypal human acute phase protein (Ganapathi et al., 1988 ; Depraetere et al., 1991). We found evidence of synergistic stimulation between the cytokines, as seen with al acid glycoprotein, and inhibition of IL6 stimulation by ILl, as seen with fibrinogen. Thus, varying levels, exposure sequence and/or mixtures of cytokines could result in different serum levels of acute phase proteins. Moreover, since IL1 induces IL6 in stromal cells, this indirect effect seems the likely mechanism for IL1 stimulation of fibrinogen in vivo. As is the case for a number of cytokines, there are other mediators that similarly regulate the hepatic acute phase response. Baumann showed that IL11 and leukemia inhibitory factor (LIF) act similarly in the liver as does IL6 (Baumann and Wong, 1989; Baumann and Schendel, 1991) and Richards showed that oncostatin M (OM) exhibits similar hepatocyte stimulation (Richards et al., 1992). The fact that four different cytokines, operating through four different ligand binding receptors on the hepatocyte, regulate the exact same set of genes and demonstrate similar synergy with IL1 and corticosteroid, suggests a common signal for gene regulation. Moreover, the cytokines initiate nuclear protein interaction with the same regulatory region(s) of the acute phase protein genes (Richards et al., 1992). Such coalescence of signal transduction suggests common intermediates and this has been supported by the recent identification of the second component of the LIF ligand-binding receptor as being identical to the molecule (gp 130) used by the IL6 ligand binding receptor (Taga et al., 1989; Hibi et al., 1990; Gearing et al., 1992). Mechanisms of IL6-mediated signal transduction in the hepatocyte are unclear but may involve GTP binding (Richards et al., 1991).
IN IiWA4UNOLOGY Other aspects of the acute phase response are also mediated in part by IL6. Like ILI, IL6 can induce a febrile response mediated by the production of prostaglandin (Rothwell et al., 1991 ; Dinarello et al., 1991). In addition, in vitro and in vivo, IL6 can induce the release of CRF, ACTH and subsequently corticosteroid by the pituitary/adrenal axis (Woloski et al., 1985; Naitoh et al., 1988). Whether any of the other three cytokines also act in this manner is not known. While the IL6-like hepatocyte-stimulating activity of the other cytokines is acknowledged, there is little data to implicate them in induction of the acute phase in vivo, and IL6 is likely the major regulator of this response. Specific antisera to IL6 can inhibit > 95 070 of the hepatocyte-stimulating activity of either LPS-stimulated monocyte- or IL 1/TNFstimulated fibroblast-conditioned medium. After trauma or infection, raised IL6 serum levels are easily detected, coincident with the onset of acute phase protein synthesis (Nijsten et al., 1987; Houssiau et al., 1988; Ohzato et al., 1992; Gauldie et al., 1990; Jablons et al., 1989). Overexpression of IL6 in transgenie systems results in the hepatic acute phase response (Akira et al., 1990; Hirano, 1992), and direct anti-inflammatory activity of IL6 is supported by recent data showing inhibition of the development of experimental arthritis in the rat (Mihara et al., 1991). The antiinflammatory aspect of IL6 action can be extended to local tissue protection as it regulates specific expression of tissue inhibitor of metalloproteinase (TIMP) in fibroblasts (Richards et al., submitted). However, attempts to block the acute phase induction activity of IL6 in experimental inflammation using inhibitory poly- and/or monoclonal antibodies have met with limited success. Complexed IL6 apparently extends the normal rapid plasma half-life of the native mediator (T’/, of 7 to 15 min) and thus may variably contribute to enhanced plasma IL6 activity when diminished levels are expected. This may explain the counterfinding of an inflammatory role for IL6 as reported for lethal E. coli infection in mice (Starnes et al., 1990). There are varying reports of the regulation of the IL6 receptor on hepatocytes in vitro (Bauer et al., 1989; Baumann et al., 1990; Rose-John et al., 1990; Schooltink et al., 1991). In vI’vo, IL6 administration to rats elicits a rapid and marked upregulation of the mRNA for the 80-kDa receptor in the liver, implying an enhancement of the response of the liver at a time when rapid deployment of the antiinflammatory acute phase proteins is most needed. Serum levels of IL6 decrease to normal 24-36 h after trauma and are accompanied by a return to normal levels of expression of hepatic IL6 receptor and normal serum levels of the acute phase proteins. Taken together, these data support the major antiinflammatory role played by IL6 in the induction
INTERLEUKIN of the very important and protective acute phase response. Whether IL6 is the only regulator in all situations, or how much is contributed by other cytokines, remains to be established. However, we suggest that administration of IL6 or induction of IL6 is an antiinflammatory approach, leading to protection against further tissue destruction and returning homeostatic balance to the system.
References Akira, S., Hirano, T., Taga, T. & Kishimoto, T. (1990), Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF). FASEB J., 4, 2860-2867. Andus, T., Geiger, T., Hirano, T., Northoff, H., Ganter, U., Bauer, J., Kishimoto,T. & Heinrich, P.C. (1987), Recombinant human B cell stimulatory factor 2 (BSF-Z/IFN-beta2) regulatesbeta-fibrinogenand albuminmRNA levelsin Fao-9cells. FEBS Letters, 221, 18-22. Bauer, J., Bauer, T.M., Kalb, T., Taga, T., Lengyel, G., Hirano, T., Kishimoto, T., Acs, G., Mayer, L. & Gerok, W. (1989),Regulationof interleukin 6 receptor expressionin human monocytesand monocytederived macrophages.Comparisonwith the expression in human hepatocytes. J. exp. Med., 170, 1537-1549. Bauer, J., Birmelin, M., Northoff, G.H., Northemann, W., Tran-Thi, T.A., Ueberberg, H., Decker, K. & Heinrich, P.C. (1984), Induction of rat alpha-2-macroglobulinin vivo and in hepatocyte primary cultures: synergisticaction of glucocorticoids and a Kupffer cell derived factor. FEBS Letters, 177, 89-94. Baumann, H. (1989), Hepatic acute phase reaction in vivo and in vitro. In vitro Cell. Dev. Biol., 25, 115-126. Baumann,H. & Gauldie, J. (1990), Regulationof hepatic acute phase plasma protein genesby hepatocyte stimulatingfactors and other mediatorsof inflammation. Mol. biol. Med., 7, 147-159. Baumann, H. & Maquat, L.E. (1986), Localization of DNA sequences involved in dexamethasonedependentexpressionof the rat al-acid-glycoprotein gene. Mol. cell. Biol., 6, 2551-2561. Baumann,H., Morella, K.K., Jahreis,G.P. & Marinkovic, S. (1990),Distinct regulation of the interleukin-1 and interleukind response elementsof the rat haptoglobin gene in rat and human hepatomacells. Mol. cell. Biol., 10, 5967-5976. Baumann, H., Onorato, V., Gauldie, J. & Jahreis,G.P. (1987a),Distinct setsof acutephaseplasmaproteins are stimulatedby separatehepatocytestimulatingfactors and monokinesin rat hepatomacells. J. biol. Chem.,
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6 Baumann,H. & Schendel,P. (1991), Interleukin-11 regulatesthe hepaticexpressionof the sameplasmaprotein genesas interleukin-6. J. biol. Chem.. 266, 20424-20427. Baumann, H. & Wong, G.G. (1989), Hepatocytestimulating factor III sharesstructural and function identity with leukemiainhibitory factor. J. Immunol., 143, 1163-1167. Baumann,M., Baumann,H. & Fey, G.H. (1990),Molecular cloning, characterization and functional expression of the rat liver interleukin-6 receptor. J. biol. Chem., 265, 19853-19862. Darlington, G.J., Wilson, D.R., Revel, M. & Kelly, J.H. (1989),Responseof liver genesto acute phasemediators. Ann. N.Y. Acad. Sci., 557, 310-316. Depraetere,S., Willems, J. & Joneau, M. (1991),Stimulation of CRP secretionin HepG2 cells: cooperative effect of dexamethasoneand interleukin-6. Agents Actions,
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Dinarello, C.A., Cannon, J.G., Mancilla, J., Bishai, I., Lees,J. & Coceani,F. (1991),Interleukin-6 asan endogenouspyrogen: induction of prostaglandinE2 in brain but not in peripheralblood mononuclearcells. Brain Res., 562, 199-206. Fey, G.H. & Gauldie, J. (1990),The acutephaseresponse of the liver in inflammation, in “Progressin liver diseases, Vol. 9” (H. Popper and F. Schaffner) (pp. 89-116). W.B. Saunders,Philadelphia. Fey, G.H., Hattori, M., Northernann,W., Abraham, L.J., Baumann,M., Braciak, T.A., Fletcher, R.G., GauIdie, J., Lee, F. & Reymond, M.F. (1989), Regulation of rat liver acute phasegenesby interleukin-6 and production of hepatocyte stimulating factors by rat hepatomacells. Ann. iV. Y. Acad. Sci., 557, 317-331. Ganapathi, M.K., May, L.T., Schultz, D., Brabenec,A., Weinstein,J., Sehgal,P.B. & Kushner,I. (1988),Role of interleukin-6 in regulatingsynthesisof C-reactive protein and serumamyloid A in human hepatoma cell lines. Biochem. biophys. Res. Commun., 157, 271-277. Gauldie, J. (1991),Acute phaseresponse,in “Encyclopedia of human biology, Vol. 1” (R. Dulbecco) (pp. 25-35). Academic Press,New York, London. Gauldie, J. & Baumann, H. (1991), Cytokines and acute phaseprotein expression,in “Cytokines and inflammation” (E.S. Kimball) (pp. 275-305).CRC Press, Boca Raton, FL. Gauldie, J., Northernann, W. & Fey, G.H. (1990), IL-6 functions asan exocrine hormonein inflammation : hepatocytes undergoing acute phase responses require exogenousIL-6. J. Immunol., 144, 38043808. Gauldie, J., Richards, C., Harnish, D., Lansdorp, P. & Baumann,H. (1987),Interferon 82/B-cellstimulatory factor type 2 sharesidentity with monocyte-derived hepatocyte-stimulatingfactor andregulatesthe major acute-phase protein responsein liver cells.Proc. natl. Acad. Sci. (Wash.), 84, 7251-7255. Gearing, D.P., Comeau, M.R., Friend, D.J., Gimpel, S.D., Thut, C. J., McGourty, J., Brasher,K.K., King, J.A., Gillis, S., Mosley, B., Ziegler, S. & Cosman, D. (1992),The IL-6 signaltransducer,gp130: an oncostatinM receptorand affinity converter for the LIF receptor. Science, 255, 1434-1437.
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Geiger, T., Andus, T., Klapproth, J., Hirano, T., Kishimoto, T. & Heinrich, P.C. (1988), Induction of rat acutephase proteins by interleukin-6 in vivo. Europ. J. Immunol., 18, 711-721. Hattori, M., Abraham, L.J., Northernann, W. & Fey, G.H. (1990), Acute-phase reaction induces a specific complex between hepatic nuclear proteins and the interleukin-6 response element of the rat aZmacroglobulin gene. Proc. null. Acad. Sci. (Wash.), 87, 2364-2368. Heinrich, P.C., Castell, J.V. & Andus, T. (1990), Interleukind and the acute phase response. Biochem. J., 265, 621-636. Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T. & Kishimoto, T. (1990), Molecular cloning and expression of an IL-6 signal transducer, gpl30. Cell, 63, 1149-1157. Hirano, T. (1992), IL-6 and its relation to inflammation and disease. Clin. Immunol. Immunopath., 62, S60-S65. Houssiau, F., Devogelaer, J.-P., Van Damme, J., Nagant de Deuxchaisnes, C. & Van Snick, J. (1988), Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritises. Arthritis Rheum., 3 1, 184-788. Jablons, D.M., Mule, J.J., McIntosh, J.K., Sehgal, P.B., May, L.T., Huang, C.M., Rosenberg, S.A. & Lotze, M.T. (1989), IL-6/1FN-P-2 as a circulating hormone. Induction by cytokine administration in humans. J. Immunol., 142, 1542-1547. Koj, A. (1974), Acute-phase reactants - their synthesis, turnover and biological significance, in “Structure and function of plasma proteins” (A.C. Allison) (p. 73). Plenum Press, London. Koj, A. (1985), Acute-phase reactants - their synthesis turnover and biological significance, in “Injury and infection” (A.H. Gordon and A. Koj) (pp. 145-160). Elsevier, Amsterdam. Koj, A., Gauldie, J., Regoeczi, E., Sauder, D.N. & Sweeney, G.D. (1984), The acute-phase response of cultured rat hepatocytes. System characterization and the effect of human cytokines. Biochem. J., 224, 505-514. Kushner, I. (1982), The phenomenon of the acute phaSe response. Ann. N. Y. Acad. Sci., 389, 39-48. Majello, B., Arcone, R., Toniatti, C. & Ciliberto, G. (1990), Constitutive and IL&induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J., 9, 457-465. Marinkovic, S., Jahreis, G.P., Wong, G.G. & Baumann, H. (1989), IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J. Immunol., 142, 808-812. Mihara, M., Ikuta, M., Koishihara, Y. & Ohsugi, Y. (1991), IL-6 inhibits delayed-type hypersensitivity and the development of adjuvant arthritis. Europ. J. Immunol., 21, 2327-2331. Morrone, G., Ciliberto, G., Oliviero, S., Arcones, R., Dente, L., Content, J. & Cortese, R. (1988), Recombinant interleukin-6 regulates the transcriptional activation of a set of human acute phase genes. J. biol. Chem., 263, 12554-12558. Naitoh, Y., Fukata, J., Tominaga, T., Nakai, Y., Tamai, S., Mori, K. & Imura, H. (1988), Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in
conscious, freely moving rats. Biochem. biophys. Res. Commun., 155, 1459-1463. Nijsten, M. W .N., de Groot, E.R., ten Duis, H. J., Hack, C.E. & Aarden, L.A. (1987), Serum levels of interleukin-6 an acute phase responses. Lancet, II, Letter : 921. Ohzato, H., Yoshizaki, K., Nishimoto, N., Ogata, A., Tagoh, H., Monden, M., Gotoh, M., Kishimoto, T. & Mori, T. (1992), Interleukin-6 as a new indicator of inflammatory status : detection of serum levels of interleukind and C-reactive protein after surgery. Surgery, 111, 201-209. Poli, V. & Cortese, R. (1989), Interleukin-6 induces a liverspecific nuclear protein that binds to the promoter of acute-phase genes. Proc. natl. Acad. Sci. (Wash.), 86, 8202-8206. Prowse, K.R. & Baumann, H. (1988), Hepatocytestimulating factor, P2-interferon, and interleukin-1 enhance ellpression of the rat al-acid glycoprotein gene via a distal upstream regulatory region. Mol. ceil. Biol., 8, 42-51. Prowse, K.R. & Baumann, H. (1990), Molecular characterization and acute-phase expression of the multiple Mus caroli al-acid glycoprotein (AGP) genes. J. biol. Chem., 265, 10201-10209. Richards, C., Brown, T.J., Shoyab, M., Baumann, H. & Gauldie, J. (1992), Recombinant oncostatin M stimulates the production of acute-phase proteins in HepG2 cells and rat primary hepatocytes in vitro. J. Immunol., 148, 1731-1736. Richards, C., Gauldie, J. & Baumann, H. (1991), Cytokine control of acute-phase protein expression. Europ. Cytokine Net., 2, 89-98. Ritchie, D.G. & Fuller, G.M. (1983), Hepatocytestimulating factor: a monocyte-derived acute-phase regulatory protein. Ann. N. Y. Acad. Sci., 408, 490-502. Rose-John, S., Schooltink, H., Lenz, D., Hipp, E., Dufhues, G., Schmitz, H., Schiel, X., Hirano, T., Kishimoto, K. & Heinrich, P.C. (1990), Studies on the structure and regulation of the human hepatic interleukind receptor. Europ. J. Biochem., 190, 19-83. Rothwell, N.J., Busbridge, N.J., LeFeuvre, R.A., Hardwick, A.J., Gauldie, J. & Hopkins, S.J. (1991), Interleukin-6 is a centrally acting endogenous pyrogen in the rat. Canad. J. Physiol. Pharmacol., 69, 1465-1469. Schooltink, H., Stoyan, T., Lenz, D., Schmitz, H., Hirano, T., Kishimoto, T., Heinrich, P.C. & Rose-John, S. (1991), Structural and functional studies on the human hepatic interleukind receptor. Biochem. J., 277, 659-664. Sonne, O., Davidson, O., Moller, B.K. & Munck, P.C. (1990), Cellular targets and receptors for IL-6. - I. In vivo and in vitro uptake of IL-6 in liver and hepatocytes. Europ. J. clin. Invest., 20, 366-376. Starnes, H.F., Pearce, M.K., Tewari, A., Yim, J.H., Zou, J. & Abrams, J.S. (1990), Anti-IL-6 monoclonal antibodies protect against lethal E. coli infection and lethal tumor necrosis factor-a challenge in mice. J. Immunol., 145, 4185-4191. Taga, T., Hibi, M., Hirata, Y., Yamasaki, K., Yasukawa, K., Matsuda, T., Hirano, T. & Kishimoto, T.
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(1989), Interleukin-6 (IL-6) triggers the association of its receptor (IL-6-R) with a possible signal transducer, gp 130. Cell, 58, 573-581. Woloski, B.M.R.N.J., Smith, E.M., Meyer, W.J. III, Fuller, G.M. & Blalock, J.E. (1985), Corticotropinreleasing activity of monokines. Science, 230, 1035-1037. Won, K.-A. & Baumann, H. (1990), The cytokine response
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element of the rat al-acid glycoprotein gene is a complex of several interacting regulatory sequences.Mol. cell. Biol., 10, 3965-3978. Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B., Taniguchi, T., Hirano, T. KcKishimoto, T. (1988), Cloning and expression of the human interleukin-6 (BSF-2/IFNP2) receptor. Science, 241. 825-828.
6 and autoimmunity
and plasma cell neoplasias
T. Hirano Division
of Molecular Oncology, Biomedical Research Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka 565 (Japan)
1. Involvement of IL6 in B-cell abnormalities chronic inflammation
in
It has been implied that chronic inflammation may induce B-cell growth and differentiation, leading to the facilitating of autoimmune disease and B-cell malignancies. Patients with pre-existing chronic inflammations show polyclonal hypergammaglobulinaemia and frequently develop plasma cell neoplasias or lymphoma (Isobe and Osserman, 197 1; Isomaki et al., 1978; Shoenfeld and Isenberg, 1988; Rook and Stanford, 1992). In animal models, mineral oil or pristane that induces chronic inflammation can elicit not only autoimmune rheumatoid arthritis, but also plasmacytoma in certain strains of mice (Potter and Boyce, 1962; Potter and Wax, 1981). Infiltration of polyclonal plasmacytosis was initially observed in the pristane-induced granulomatous tissue, and subsequently plasmacytoma, generated exclusively in the inflammatory lesion. The evidence strongly suggested the role of inflammatory cells in polyclonal plasmacytosis and the generation of plasma cell neoplasias, although the mechanisms had not been well documented until the molecular cloning of interleukin 6 (IL6). IL6 is a multifunctional cytokine involved in immune response, inflammation and haematopoiesis, which is a growth- and/or differentiation-inducing factor (Sehgal et al., 1989; Hirano and Kishimoto, 1990; Van Snick, 1990). In relation to the role of inflammatory cells in the pathogenesis of polyclonal
Center,
B-cell abnormalities and malignancies, IL6 was identified as a factor produced by virus-infected cells (Weissenbach et al., 1980) or inflammatory cells infiltrated in pleural effusion of patients with pulmonary tuberculosis (TB) (Teranishi et al., 1982) and an inflammatory cytokine, ILl, an inducible 26-kDa protein (Haegeman et al., 1986). Furthermore, B-cell differentiation factor (Hirano et al., 1985, 1986) and plasmacytoma/hybridoma/myeloma growth factor (Van Damme et al., 1987; Van Snick et al., 1988; Aarden et al., 1985; Nordan and Potter, 1986; Kawano et al., 1988), both of which had been independently investigated, turned out to be an identical molecule, IL6. In addition, hepatocytestimulating factor which regulates the biosynthesis of a variety of acute phase proteins was also found to be identical with IL6 (Gauldie et al., 1987). These facts indicate that one molecule, IL6, which is produced by inflammatory cells such as antigenactivated lymphocytes and/or macrophages, virusinfected fibroblast, and/or lymphocytes and pristanestimulated macrophages, is a real molecule governing both the immune response leading to B-cell growth and differentiation into plasma cells and the acute-phase reaction. The other critical finding relevant to the involvement of IL6 in B-cell abnormalities was obtained in patients with cardiac myxoma who showed a variety of autoimmune symptoms, such as hypergammaglobulinaemia, the presence of autoantibodies and an increase in acute phase proteins, all of which disappeared after the resection of