Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Aug 15, 1992; 89(16): 7375–7379.

Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice.


Both tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) are found in synovial fluid from arthritic joints of humans and of rodents with experimental arthritis. The role of endogenously produced TGF-beta and TNF in the pathogenesis of collagen type II-induced arthritis (CIA) in DBA/1 mice was examined by determining the effect of neutralizing monoclonal antibodies to these factors on the course of the disease. Endogenously produced as well as systemically administered TGF-beta 1 and TNF-alpha had opposite effects, since TGF-beta 1 and anti-TNF protected against CIA, whereas anti-TGF-beta and TNF-alpha increased CIA incidence and/or severity. Intraperitoneally injected TGF-beta 1 at a dose of 2 micrograms per day for 14 days significantly ameliorated arthritis, even when started at the time of arthritis development, although it did not reverse established disease. The resistance to CIA induction caused by a prior intravenous injection of collagen type II was not significantly influenced by the simultaneous injection of TGF-beta 1, TNF-alpha, or interleukin 1 alpha. It is concluded that the endogenous production of TNF and TGF-beta is important in determining the course of CIA.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7443–7446. [PMC free article] [PubMed]
  • Cremer MA, Hernandez AD, Townes AS, Stuart JM, Kang AH. Collagen-induced arthritis in rats: antigen-specific suppression of arthritis and immunity by intravenously injected native type II collagen. J Immunol. 1983 Dec;131(6):2995–3000. [PubMed]
  • Nagler-Anderson C, van Vollenhoven RF, Gurish MF, Bober LA, Siskind GW, Thorbecke GJ. A cross-reactive idiotype on anti-collagen antibodies in collagen-induced arthritis: identification and relevance to disease. Cell Immunol. 1988 May;113(2):447–461. [PubMed]
  • van Vollenhoven RF, Nagler-Anderson C, Soriano A, Siskind GW, Thorbecke GJ. Tolerance induction by a poorly arthritogenic collagen II can prevent collagen-induced arthritis. Cell Immunol. 1988 Aug;115(1):146–155. [PubMed]
  • Arita C, Kaibara N, Hotokebuchi T, Takagishi K, Arai K. Effect of cyclophosphamide and its analogs on collagen arthritis in rats. Clin Immunol Immunopathol. 1987 Jun;43(3):354–361. [PubMed]
  • Takagishi K, Kaibara N, Hotokebuchi T, Arita C, Morinaga M, Arai K. Effects of cyclosporin on collagen induced arthritis in mice. Ann Rheum Dis. 1986 Apr;45(4):339–344. [PMC free article] [PubMed]
  • Ranges GE, Sriram S, Cooper SM. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J Exp Med. 1985 Sep 1;162(3):1105–1110. [PMC free article] [PubMed]
  • Banerjee S, Wei BY, Hillman K, Luthra HS, David CS. Immunosuppression of collagen-induced arthritis in mice with an anti-IL-2 receptor antibody. J Immunol. 1988 Aug 15;141(4):1150–1154. [PubMed]
  • Cooper SM, Sriram S, Ranges GE. Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma. J Immunol. 1988 Sep 15;141(6):1958–1962. [PubMed]
  • Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. [PMC free article] [PubMed]
  • Ristow HJ. BSC-1 growth inhibitor/type beta transforming growth factor is a strong inhibitor of thymocyte proliferation. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5531–5533. [PMC free article] [PubMed]
  • Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed]
  • Kehrl JH, Taylor AS, Delsing GA, Roberts AB, Sporn MB, Fauci AS. Further studies of the role of transforming growth factor-beta in human B cell function. J Immunol. 1989 Sep 15;143(6):1868–1874. [PubMed]
  • Espevik T, Figari IS, Shalaby MR, Lackides GA, Lewis GD, Shepard HM, Palladino MA., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. [PMC free article] [PubMed]
  • Chantry D, Turner M, Abney E, Feldmann M. Modulation of cytokine production by transforming growth factor-beta. J Immunol. 1989 Jun 15;142(12):4295–4300. [PubMed]
  • Straub C, Zubler RH. Immortalization of EBV-infected B cells is not influenced by exogenous signals acting on B cell proliferation. Effects of mutant EL-4 thymoma cells and transforming growth factor-beta. J Immunol. 1989 Jan 1;142(1):87–93. [PubMed]
  • Shalaby MR, Ammann AJ. Suppression of immune cell function in vitro by recombinant human transforming growth factor-beta. Cell Immunol. 1988 Apr 1;112(2):343–350. [PubMed]
  • Quere P, Thorbecke GJ. Multiple suppressive effects of transforming growth factor beta 1 on the immune response in chickens. Cell Immunol. 1990 Sep;129(2):468–477. [PubMed]
  • Rook AH, Kehrl JH, Wakefield LM, Roberts AB, Sporn MB, Burlington DB, Lane HC, Fauci AS. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol. 1986 May 15;136(10):3916–3920. [PubMed]
  • Ranges GE, Figari IS, Espevik T, Palladino MA., Jr Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987 Oct 1;166(4):991–998. [PMC free article] [PubMed]
  • Espevik T, Figari IS, Ranges GE, Palladino MA., Jr Transforming growth factor-beta 1 (TGF-beta 1) and recombinant human tumor necrosis factor-alpha reciprocally regulate the generation of lymphokine-activated killer cell activity. Comparison between natural porcine platelet-derived TGF-beta 1 and TGF-beta 2, and recombinant human TGF-beta 1. J Immunol. 1988 Apr 1;140(7):2312–2316. [PubMed]
  • Belsito DV, Epstein SP, Schultz JM, Baer RL, Thorbecke GJ. Enhancement by various cytokines or 2-beta-mercaptoethanol of Ia antigen expression on Langerhans cells in skin from normal aged and young mice. Effect of cyclosporine A. J Immunol. 1989 Sep 1;143(5):1530–1536. [PubMed]
  • Epstein SP, Baer RL, Thorbecke GJ, Belsito DV. Immunosuppressive effects of transforming growth factor beta: inhibition of the induction of Ia antigen on Langerhans cells by cytokines and of the contact hypersensitivity response. J Invest Dermatol. 1991 Jun;96(6):832–837. [PubMed]
  • Lotz M, Kekow J, Carson DA. Transforming growth factor-beta and cellular immune responses in synovial fluids. J Immunol. 1990 Jun 1;144(11):4189–4194. [PubMed]
  • Lafyatis R, Thompson NL, Remmers EF, Flanders KC, Roche NS, Kim SJ, Case JP, Sporn MB, Roberts AB, Wilder RL. Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats. Studies on secretion by synovial fibroblast-like cells and immunohistologic localization. J Immunol. 1989 Aug 15;143(4):1142–1148. [PubMed]
  • Allen JB, Manthey CL, Hand AR, Ohura K, Ellingsworth L, Wahl SM. Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta. J Exp Med. 1990 Jan 1;171(1):231–247. [PMC free article] [PubMed]
  • Ruddle NH, Bergman CM, McGrath KM, Lingenheld EG, Grunnet ML, Padula SJ, Clark RB. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med. 1990 Oct 1;172(4):1193–1200. [PMC free article] [PubMed]
  • Selmaj K, Raine CS, Cross AH. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol. 1991 Nov;30(5):694–700. [PubMed]
  • Kuruvilla AP, Shah R, Hochwald GM, Liggitt HD, Palladino MA, Thorbecke GJ. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918–2921. [PMC free article] [PubMed]
  • Pennica D, Hayflick JS, Bringman TS, Palladino MA, Goeddel DV. Cloning and expression in Escherichia coli of the cDNA for murine tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6060–6064. [PMC free article] [PubMed]
  • Kramer SM, Carver ME. Serum-free in vitro bioassay for the detection of tumor necrosis factor. J Immunol Methods. 1986 Nov 6;93(2):201–206. [PubMed]
  • Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. [PubMed]
  • Lucas C, Bald LN, Fendly BM, Mora-Worms M, Figari IS, Patzer EJ, Palladino MA. The autocrine production of transforming growth factor-beta 1 during lymphocyte activation. A study with a monoclonal antibody-based ELISA. J Immunol. 1990 Sep 1;145(5):1415–1422. [PubMed]
  • Sheehan KC, Ruddle NH, Schreiber RD. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed]
  • Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med. 1977 Sep 1;146(3):857–868. [PMC free article] [PubMed]
  • Wood FD, Pearson CM, Tanaka A. Capacity of mycobacterial wax D and its subfractions to induce adjuvant arthritis in rats. Int Arch Allergy Appl Immunol. 1969;35(5):456–467. [PubMed]
  • Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med. 1988 Mar 1;167(3):1067–1085. [PMC free article] [PubMed]
  • Weigle WO, Scheuer WV, Hobbs MV, Morgan EL, Parks DE. Modulation of the induction and circumvention of immunological tolerance to human gamma-globulin by interleukin 1. J Immunol. 1987 Apr 1;138(7):2069–2074. [PubMed]
  • Hom JT, Butler LD, Riedl PE, Bendele AM. The progression of the inflammation in established collagen-induced arthritis can be altered by treatments with immunological or pharmacological agents which inhibit T cell activities. Eur J Immunol. 1988 Jun;18(6):881–888. [PubMed]
  • Lindblad S, Klareskog L, Hedfors E, Forsum U, Sundström C. Phenotypic characterization of synovial tissue cells in situ in different types of synovitis. Arthritis Rheum. 1983 Nov;26(11):1321–1332. [PubMed]
  • Zvaifler NJ, Steinman RM, Kaplan G, Lau LL, Rivelis M. Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis. J Clin Invest. 1985 Aug;76(2):789–800. [PMC free article] [PubMed]
  • Zuber P, Kuppner MC, De Tribolet N. Transforming growth factor-beta 2 down-regulates HLA-DR antigen expression on human malignant glioma cells. Eur J Immunol. 1988 Oct;18(10):1623–1626. [PubMed]
  • Czarniecki CW, Chiu HH, Wong GH, McCabe SM, Palladino MA. Transforming growth factor-beta 1 modulates the expression of class II histocompatibility antigens on human cells. J Immunol. 1988 Jun 15;140(12):4217–4223. [PubMed]
  • Ding A, Nathan CF, Graycar J, Derynck R, Stuehr DJ, Srimal S. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol. 1990 Aug 1;145(3):940–944. [PubMed]
  • Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. [PMC free article] [PubMed]
  • Karpus WJ, Swanborg RH. CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta. J Immunol. 1991 Feb 15;146(4):1163–1168. [PubMed]
  • Sporn MB, Roberts AB, Wakefield LM, Assoian RK. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. [PubMed]
  • Hiraki Y, Inoue H, Hirai R, Kato Y, Suzuki F. Effect of transforming growth factor beta on cell proliferation and glycosaminoglycan synthesis by rabbit growth-plate chondrocytes in culture. Biochim Biophys Acta. 1988 Apr 2;969(1):91–99. [PubMed]
  • Hom JT, Bendele AM, Carlson DG. In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice. J Immunol. 1988 Aug 1;141(3):834–841. [PubMed]
  • Dubois CM, Ruscetti FW, Palaszynski EW, Falk LA, Oppenheim JJ, Keller JR. Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J Exp Med. 1990 Sep 1;172(3):737–744. [PMC free article] [PubMed]
  • Turner M, Chantry D, Katsikis P, Berger A, Brennan FM, Feldmann M. Induction of the interleukin 1 receptor antagonist protein by transforming growth factor-beta. Eur J Immunol. 1991 Jul;21(7):1635–1639. [PubMed]
  • Arend WP, Welgus HG, Thompson RC, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. [PMC free article] [PubMed]
  • Louis JA, Chiller JM, Weigle WO. The ability of bacterial lipopolysaccharide to modulate the induction of unresponsiveness to a state of immunity. Cellular parameters. J Exp Med. 1973 Dec 1;138(6):1481–1495. [PMC free article] [PubMed]
  • Myers LK, Stuart JM, Kang AH. A CD4 cell is capable of transferring suppression of collagen-induced arthritis. J Immunol. 1989 Dec 15;143(12):3976–3980. [PubMed]
  • Parks DE, Doyle MV, Weigle WO. Induction and mode of action of suppressor cells generated against human gamma globulin. I. An immunologic unresponsive state devoid of demonstrable suppressor cells. J Exp Med. 1978 Sep 1;148(3):625–638. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...