Type I and Type II Interferons Upregulate Functional Type I Interleukin ...

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 15:1065-1073 (1995)

Mary

Ann

Lieber!,

Inc.

I and Type II Interferons Upregulate Functional Type I Interleukin-1 Receptor in a Human Fibroblast Cell Line TIG-1

Type

TAKEMASA TAKII, NORIYUKI NIKI, DE YANG, HIROAKI KIMURA, ATSUSHI ITO, HIDETOSHI HAYASHI, and KIKUO ONOZAKI

ABSTRACT The regulation of type I interleukin-1 receptor (IL-1R) expression by type I, interferon (IFN)-a A/D, and type II IFN, IFN-y, in a human fibroblast cell line TIG-1 was investigated. After 2 h stimulation with human IFN-a A/D or IFN-y, the levels of type IIL-1R mRNA increased. We previously reported that IL-1 upregulates transcription and cell surface molecules of type I IL-1R in TIG-1 cells through induction of prostaglandin (PG) E2 and cAMP accumulation. However, indomethacin was unable to inhibit the effect of IFNs, indicating that IFNs augment IL-1R expression through a pathway distinct from that of IL-1. The augmentation was also observed in other fibroblast cell lines. Nuclear run-on assays and studies of the stability of mRNA suggested that the increase in IL-1R mRNA was a result of the enhanced transcription of IL-1R gene. Binding studies using I2SI-IL-la revealed that the number of cell surface IL-1R increased with no change in binding affinity by treatment with these IFNs. Pretreatment of the cells with D7Ns enhanced IL-1-induced IL-6 production, indicating that IFNs upregulate functional IL-1R. IL-1 and IFNs are produced by the same cell types, as well as by the adjacent different cell types, and are concomitantly present in lesions of immune and inflammatory reactions. These results therefore suggest that IFNs exhibit synergistic effects with IL-1 through upregulation of IL-1R. Augumented production of IL-6 may also contribute to the reactions.

INTRODUCTION

(IL-1) play Interleuken-Iresponse.'''

s an important role in host defense IL-1 exhibits a variety of biologic actypes,'2' for example, induction of hormones, cytokines, prostanoids, leukotrienes, and NO. Two types of IL-1 have been identified, a and ßPA) They have the same molecular weight, 17 kD, but differ in isoelectric point. The IL-1 signal is transduced through its specific receptor expressed on the cell surface. Two types of IL-1 receptor (IL-1R) exist'5-6': the type I receptor is mainly expressed in T cells and fibroblasts, and the type II receptor is mainly expressed in B cells and macrophages. The molecular weights of these receptors are 80 and 60 kD, respectively. Two types of IL-1 are able to bind to these IL-1 receptors with different affinities. Recent studies revealed that type II receptor is a decoy receptor and only type I receptor transduces the IL-1 signal.'7' Therefore, the effect of IL-1 is regulated at both the production and receptor levels. The cytokines IL-1, IL-3, and IL-4, transforming growth factor ß, granulocyte colony-stimulating factor (CSF), macrophage CSF, and

and immune tivities for various cell

granulocyte-macrophage CSF, and a growth factor, platelet-derived growth factor, were reported to regulate IL-1R expression at the mRNA and cell surface molecular levels.'8-13'

We previously reported that IL-1 upregulates type I IL-1 R at both mRNA and cell surface levels in a human fibroblast cell line, TIG-1."4' The IL-1 effect was mediated through induction of prostaglandin E2 (PGE2) synthesis followed by intracellular cAMP accumulation. Therefore, this IL-1 effect is inhibited by indomethacin, an inhibitor of cyclooxygenäse. In contrast, in the presence of indomethacin, IL-1 downregulates IL-1R mRNA by destabilizing the mRNA in the same cells."5' Therefore, IL-1 dually regulates IL-1R expression in fibroblasts. Interferon (IFN) was initially found to be a factor exhibiting a defensive effect for bacterial or virus infection,"6' and it is now realized to play an important role in immunologie and inflammatory reactions"7' and defense against cancer."819' IFN-a, ß, and (o are called type I IFN, and IFN-y is called type II IFN. Type I and type II IFNs bind to different receptors.'20' However, most of their biologic activities are similar. IFNs are therapeutically useful for many virus-related diseases, such as hepatitis B virus

Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya 467, Japan.

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TAKII ET AL.

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(HBV)'2" and hepatitis C virus (HCV), 3

a

Ü

c 3

O

O

S

m

a

c 3

O ffl

0

125|-IL-1a(nM)

2

Bound

4

Molecules/cell

6

(X10-3)

FIG. 6. Scatchard plot analysis of specifically bound l25I-IL-la to TIG-1 cells. TIG-1 (confluent state in a six-well plate) were precultured with 1 /xg/ml of indomethacin for 24 h. The cells were cultured in medium containing indomethacin without (open circles) or with IFN-a A/D (solid circles; 1000 U/ml) or IFN-y (triangles; 1000 U/ml) for 4 h. Subsequently, the binding assay was conducted as described in Materials and Methods, (a) Specific binding was determined by subtracting counts bound in the presence of 800-fold excess unlabeled IL-1 a from counts bound in the presence of labeled IL-1 a alone, (b) Scatchard plot analysis of data from panel a. The labeled efficiency of IL-la was 28.8 mCi/mg protein.

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UPREGULATION OF FUNCTIONAL TYPE I IL-1R BY IFNs

4

8

12

16

20

24

IFN-a A/D Pretreated Time (hr)

4

8

IFN-y

Pretreated Time

12

16

20

24

(hr)

FIG. 7. IL-1-induced IL-6 production from IFN-pretreated TIG-1 cells. TIG-1 cells (confluent state in a 96-well plate) were precultured in medium with or without (a) IFN-a A/D ( 1000 U/ml) or (b) IFN-y ( 1000 U/ml) for the indicated period. After washing were cultured in the medium with IL-1 a ( 100 U/ml) for 24 h. The IL-6 level of the culture supernatant was measured by proliferation of the IL-6-dependent cell line.

out the medium, the cells

problems for IFNs therapy.'43' Most of them are also observed in administered IL-1.'44' Therefore, it is possible that the patients quired. IFNs upregulated the expression of not only type I IL-1R deleterious effects are augmented by synergistic actions between mRNA but also cell surface IL-1R. As shown in the previous pa- IFNs and IL-1. In the lesions of immunologie and inflammatory per,"4' TIG-1 cells expressed only type IIL-1R. In this study, its reactions, both cytokines are produced by the same cell types as affinity was 2.58 X 10"10 M and these were 3.10 X 103 well as by the adjacent different cell types. Therefore, it is possisites/cell. Both IFN-a A/D and IFN-y upregulated the number of ble that these two cytokines modulate immunologie and inflamcell surface IL-1R, 5.50 X 103 and 5.80 X 103 sites per cell, re- matory reactions. IFN-a has been reported to enhance IL-1R anspectively, without any alteration of affinity. This result reflects tagonist (IL-IRa) production in patients in vivo, and IFN-a or transcription level. In addition, IL-1-induced IL-6 production IFN-y stimulated the production of IL-IRa in peripheral blood mononuclear cells in vitroS45) This may represent a feedback was also augmented by pretreatment with IFNs. Therefore, IFNs mechanism of IFNs. IL-6 is known to exhibit a variety of effects appeared to enhance functional IL-1R expression. The IFNs effect was observed in other human fibroblast cell on reactions by affecting the function of IL-1 or IFN-producing lines, MRC-5 and MRC-9. This result indicates that the IFN ef- cells, including macrophages and fibroblasts.'46-47' Therefore, the fect is not restricted to TIG-1 cells. It is known that IL-1 and enhanced production of IL-6 may contribute to the actions of IFNs exhibit synergistic effects, including inhibition of cell pro- IL-1 and IFNs and form the complex cytokine network. liferation,'23' induction of differentiation,'24' MHC antigen,'25' and nitric oxide synthase expression,'26' inhibition of angiogeneACKNOWLEDGMENTS sis,'27' and induction of IL-6.'28' Therefore, the synergistic effect can be explained by the effects of IFNs on IL-1R expression. This work was supported in part by grants from the Ministry However, we do not rule out the possibility that the effects of IFN are postreceptor modifications of IL-1 signaling pathways. of Education, Science and Culture of Japan and the Tohkai Foundation for Technology. It is reported that IFNs downregulate IL-8 gene expression by IL-1 or tumor necrosis factor a (TNF-a) in human diploid fibroblasts.'4" In these experiments, however, the cells were Therefore, in either

case

de

novo

protein synthesis

is not re-

-

treated with both IFNs and IL-1 or IFNs and TNF. Therefore, IFNs may modulate the postreceptor signaling pathways of IL-1 and TNF. Indeed, in our experiment IL-6 production was not augmented when cells were treated with both IFNs and IL-1. Our findings seem important in considering the immunomodulating and pathophysiologic actions of IFNs. IFNs have been used for bacterial or virus infections, for example HBV,(2"HCV,'22> and human immunodeficiency virus,'42' and cancer therapy."8' The therapeutic effects of IFNs are remarkable. In type C hepatitis, IFNs are the only therapeutic medication. However, many deleterious effects of IFNs have been reported, including fever,

headache, diarrhea, vomiting, weight loss, languor, alopecia, and mental disorders. These deleterious effects

are

very serious

REFERENCES

OPPENHEIM, J.J., KOVACS, E.J., MATSUSHIMA, K„ and DURUM, S.K. (1986). There is more than one interleukin 1. Immunol. Today 7,45-56. DINARELLO, C.A. (1989). Interleukin-1 and its biologically related cytokines. Adv. Immunol. 44,153-205.

LOMEDICO, P.T., GUBLER, U, HELLMANN, C.P., DUKOVICH, M., GIRI, J.G., PAN Y.C.E., COLLIER, K., SEMIONOW, R., CHUA, A.O., and MIZEL, S.B. (1984). Cloning and

expression of murine Nature 312,458-462.

interleukin-1 cDNA in Escherichia coli.

MARCH, C.J., MOSLEY, B., LARSEN, A., CERRETTI, D.P., BRAEDIT, G., PRICE, V., GILLIS, S., HENNEY, C.S., KRON-

1072

TAKII ET AL.

HEIM, S.R., GRABSTEIN, K., CONLON, P.J., HOPP, T.P., and COSMAN, D. (1985). Cloning, sequence and expression of two distinct human interleukin-1 641-647.

complementary

DNAs. Nature

315,

5. SIMS, J.E., MARCH, C.J., COSMAN, D., WIDMER, M.B., MAC-

DONALD, H.R., McMAHAN, C.J., GRUBIN, CE., WIGNALL, J.M., JACKSON, J.L., CALL, S.M., FRIEND, D„ ALPERT, A.R., GILLIS, S., URDAL, D.L., and DOWER, S.K. (1988). cDNA expression cloning of the IL-1 receptor, a member of immunoglobulin

superfamily. Science 241,585-589.

Mechanism of interferon action in hairy cell leukemia: a model of effective cancer biotherapy. Cancer Res. 52, 1056—1066. 20. NOVICK, D., COHEN, B„ and RUBINSTEIN, M. (1994). The human interferon a/ß receptor: characterization and molecular cloning. Cell 77,391-400.

21. DUSHEIKO,

G., DIBISCEGLIE, A., BOWYER, S., SACHS, E., RITCHIE, M., SCHOUB, B., and KEW, M. (1985). Recombinant

leukocyte interferon treatment of chronic hepatitis B. Hepatology 5, 556-560. 22. DI BISCEGLIE, A.M., MARTIN, P., KASSIANIDES, C,

6. McMAHAN, C.J., SLACK, J.L., MOSLEY, B., COSMAN, D.,

LUPTON, S.D., BRUNTON, L.L., GRUBIN, CE., WIGNALL, J.M., JENKINS, N.A., BRANNAN, C.I., JENKINS, N.G., BRANNAN, C.I., COPELAND, N.G., HUEBNER, K., CROCE, CM., CANNIZZARRO, L.A., BENJAMIN, D., DOWER, S.K., SPRIGGS, M.K., and SIMS, J.E. (1991). A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 10,2821-2832.

COLOTTA, F., RE, F., MUZIO, M„ BERTINI, R., POLENTARUTTI, N., SIRONI, M., GIRI, J.G., DOWER, S.K., SIMS, J.E., and MANTOVANI, A. (1993). Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261, 472^165. 8. SHIEH, J.H., PETERSON, R.H., and MOORE, M.A. (1993). Cytokines and dexamethasone modulation of IL-1 receptors on human neutrophils in vitro. J. Immunol. 150,3515-3524. 9. GRENFELL, S.J., SMITHERS, N., and SOLARI, R. (1992). Acute upregulation of interleukin-1 receptor by ligand. Cytokine 4, 7.

114-124. 10. KOCH, K.-C, YE, K., CLARK, B.D., and DINARELLO, C.A. (1992). Interleukin 4 (IL) 4 up-regulates gene and surface IL 1 receptor type I in murine T helper type 2 cells. Eur. J. Immunol. 22, 153-157. 11. AKAHOSHI, T., OPPENHEIM, J.J., and MATSUSHIMA, K. (1988). Interleukin 1 stimulates its own receptor expression on human fibroblasts through the endogenous production of prostaglandin(s). J. Clin. Invest. 82,1219-1224. 12. DUBOIS, CM., RUSCETTI, F.W., PALASZYNSKI, E.W., FALK, L.A., OPPENHEIM, J.J., and KELLER, J.R. (1990). Transforming growth factor ß is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J. Exp. Med. 172,737-744. 13. BONIN, P.D., and SINGH, J.P. (1988). Modulation of interleukin-1 receptor expression and interleukin-1 response in fibroblasts by platelet-derived growth factor. J. Biol. Chem. 263, 11052-11055. 14. TAKII, T., AKAHOSHI, T., KATO, K., HAYASHI, H., MARUNOUCHI, T., and ONOZAKI, K. (1992). Interleukin-1 upregulates transcription of its own receptor in a human fibroblast cell line TIG-1 : role of endogenous PGE2 and cAMP. Eur. J. Immunol.

22,1221-1227.

15. TAKII, T., HAYASHI, H., MARUNOUCHI, T., and ONOZAKI, K. (1994). Interleukin-1 down-regulates type I interleukin 1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E2 synthesis. Lymphokine Cytokine Res. 13, 213-219. 16. GRESSER, I., TOVEY, M.G., BANDU, M.E., MAURY, C, and BROUTY-BOYE, D. (1976). Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. I. Rapid evolution of encephalomyocarditis. J. Exp. Med. 144,1305-1315. 17. PESTKA, S., LANGER, J.A., ZOON, K.C, and SAMUEL, CE. (1987). Interferons and their actions. Annu. Rev. Biochem. 56, 727-777.

18. HANSEN, R.M., and BORDEN, EC (1992). Current status of interferons in the treatment of cancer. Oncol. Huntingt 6,19-24. 19. VEDANTHAM, S., GAMLIEL, H., and GOLOMB, H.M. (1992).

LISKER-MELMAN, M„ MURRAY, L., WAGGONER, J., GOODMAN, Z., BANKS, S.M., and HOOFNAGLE, J.H. (1989). Recombinant interferon

a

therapy

for chronic

hepatitis

C. A

ran-

domized, double-blind, placebo-controlled trial. N. Engl. J. Med.

321,1506-1510.

23. TAKIKAWA, O., OKU, T., YASUI, H., and YOSHIDA, R. (1993). Synergism between IFN-y and IL-1 alß in growth inhibition of an allografted tumor. J. Immunol. 151,2070-2076. 24. ONOZAKI, K., URAWA, H., TAMATANI, T., IWAMURA, Y., HASHIMOTO, T., BABA, T., SUZUKI, H., YAMADA, M., YAMAMOTO, S., OPPENHEIM, J.J., and MATSUSHIMA, K. ( 1988). Synergistic interactions of interleukin 1, interferon-^, and tumor necrosis factor in terminally differentiating a mouse myeloid leukemic cell line (Ml). Evidence that interferon-/3 is an autocrine differentiating factor. J. Immunol. 140,112-119. 25. MALE, D., and PRYCE, G. (1988). Synergy between interferons and monokines in MHC induction on brain endothelium. Immunol. Lett. 17,267-271. 26. GELLER, D.A., NUSSLER, A.K., DI-SILVIO, M., LOWEN-

STEIN, C.J., SHAPIRO, R.A., WANG, S.C., SIMMONS, R.L., and BILLIAR, T.R. (1993). Cytokines, endotoxin, and glucocorticoids

regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc. Nati. Acad. Sei. USA 90,522-526. 27. NORIOKA, K„ MITAKA, T., MOCHIZUKI, Y., HARÁ, M., KAWAGOE, M., and NAKAMURA, H. (1994). Interaction of interleukin-1 and interferon-y on fibroblast growth factor-induced angiogenesis. Jpn. J. Cancer Res. 85,522-529. 28. GALY, A.H.M., and SPITS, H. (1991). IL-1, IL-4 and JPN-ydifferentially regulate cytokine production and cell surface molecule expression in cultured human thymic epithelial cells. J. Immunol. 147, 3823-3830. 29. COLLART, M.A., BELIN, D., VASSALLI, J.-D., DE-KOSSODO, S., and VASSALLI, P. (1986). y Interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J. Exp. Med. 164,2113-2118. 30. CHOMCZYNSKI, P., and SACCHI, N. (1987). Single-step method of RNA isolation by acid guanidium. Anal. Biochem. 162,156-159. 31. CELANO, P., BAYLIN, S.B., and CASERO, R.A., JR. (1989). Polyamines differentially modulate the transcription of growth-associated genes in human colon carcinoma cells. J. Biol. Chem. 264, 8922-8927. 32. KAWANO, K, HIRANO, T., MATSUDA, T., TAGA, T., HORII,

Y., IWATO, K„ ASAOKU, H., TANG, B., TANABE, O., TANAKA, H., KURAMOTO, A., and KISHIMOTO, T. (1988).

generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332,83-85. MOSSMANN, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity. J. Immunol. Methods 65,55-63. Autocrine

33.

34. HIRANO, T., AKIRA, S., TAGA, T., and KISHIMOTO, T. (1990). Biological and clinical aspects of interleukin 6. Immunol. Today 11, 443-449. 35. KIMCHI, A., SHULMAN, L., SCHMIDT, A., CHERNAJOVSKY, Y., FRADINM, A., and REVEL, M. (1979). Kinetics of the induction of three translation-regulatory enzymes by interferon. Proc. Nati. Acad. Sei. USA 76,3208-3212.

1073

UPREGULATION OF FUNCTIONAL TYPE I IL-1R BY IFNs 36. GIESE, M., and KIRCHNER, H. (1988). Interferons and their effects. Onkologie 11,151-154. 37. GIACOMINI, P., FISHER, P.B., DUIGOU, G.J., GAMBARI, R., and NATALI, P.G. (1988). Regulation of class II MHC gene expression by interférons: insights into the mechanism of action of interferon (review). Anticancer Res. 8,1153-1161. 38. HARADA, H., TAKAHASHI, E., ITOH, S., HARADA, K., HORI, T.A., and TANIGUCHI, T. (1994). Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Mol. Cell Biol. 14,1500-1509. 39. SCHINDLER, C, FU, X.Y., IMPROTA, T., AEBERSOLD, R., and DARNELL, J.E., Jr. ( 1992). Proteins of transcription factor ISGF-3: one gene encodes the 91 and 84-kDa ISGF-3 proteins that are activated by IFN a. Proc. Nati. Acad. Sei. USA 89,7836-7839. 40. YE, K., DINARELLO, CA., and CLARK, B.D. (1993). Identification of the promoter region of human interleukin 1 type I receptor gene: multiple interaction sites, high G + C content, and constitutive expression. Proc. Nati. Acad. Sei. USA 90,2295-2299. 41. OLIVEIRA, I.C, SCIAVOLINO, P.J., LEE, T.H., and VILCEK, J. (1992). Downregulation of interleukin 8 gene expression in human fibroblasts: unique mechanism of transcriptional inhibition by interferon. Proc. Nati. Acad. Sei. USA 89,9049-9053. 42. JORDAN, W.C. (1994). Three open-label studies of oral interferon a in the treatment of HIV disease. J. Nati. Med. Assoc. 86,257-262. 43. DOGANAY, M. (1983). Review of the recent advances on interferon and interferon therapy. Mikrobiol. Bull. 17,69-73. -

44. DINARELLO, CA., IKEJIMA, T., WARNER, S.J.C, ORENCOLE, S.F., LONNEMANN, G, CANNON, J.G., and LIBBY, P. (1987). Interleukin 1 induces interleukin 1.1. Induction of circulating interleukin 1 in rabbits in vivo and human mononuclear cells in vitro. J. Immunol. 139,1902-1910. 45. TILG, H., MIER, J.W., VOGEL, W., AULITZKY, W.E., WIEDERMANN, C.J., VANNIER, E., HUBER, C, and DINARELLO, CA. (1993). Induction of circulating IL-1 receptor antagonist by IFN treatment. J. Immunol. 150,4687-4692. 46. ADERKA, D., LE, J., and VILCEK, J. (1989). IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J. Immunol. 143, 3517-3523. 47. FRIES, K.M., FELCH, M.E., and PHIPPS, R.P. (1994). Interleukin6 is an autocrine growth factor for murine lung fibroblast subsets. Am. J. Respir. Cell Mol. Biol. 11,552-560.

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Department of Hygienic Chemistry Faculty of Pharmaceutical Sciences Nagoya City University Mizuho, Nagoya 467, Japan Received 7 June

1995/Accepted 8 August 1995