• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Jan 2004; 63(1): 43–49.
PMCID: PMC1754734

Interferon ß stimulates interleukin 1 receptor antagonist production in human articular chondrocytes and synovial fibroblasts


Background: Interferon (IFN) ß displays anti-inflammatory and immunosuppressive activity and has been considered for the treatment of rheumatoid arthritis (RA). Information about the effects of this molecule on joint cells is scarce, however.

Objective: To investigate the effects of IFNß on the production of interleukin-1 receptor antagonist (IL1Ra) in human articular chondrocytes and synovial fibroblasts.

Methods: Chondrocytes and synovial fibroblasts were stimulated with IFNß alone or in combination with interleukin (IL) 1ß. IL1Ra concentrations in culture supernatants and cell lysates were determined by ELISA. Expression of mRNA encoding the secreted sIL1Ra or the intracellular icIL1Ra1 isoforms was quantified by real time reverse transcriptase-polymerase chain reaction.

Results: In chondrocytes, IFNß alone had no effect, but dose dependently enhanced the secretion of IL1Ra induced by IL1ß. Chondrocyte cell lysates contained undetectable or low levels of IL1Ra, even after stimulation with IL1ß and IFNß. Consistently, IL1ß and IFNß induced sIL1Ra mRNA expression in chondrocytes, while expression of icIL1Ra1 was not detectable. Human articular chondrocytes thus mainly produce secreted IL1Ra. In synovial fibroblasts, IFNß alone dose dependently increased IL1Ra secretion. In addition, IFNß enhanced the stimulatory effect of IL1ß on IL1Ra production. In synovial cell lysates, IFNß and IL1ß also increased IL1Ra levels. Consistently, IFNß and IL1ß induced the expression of both sIL1Ra and icIL1Ra1 mRNA in synovial fibroblasts.

Conclusion: IFNß increases IL1Ra production in joint cells, which may be beneficial in cartilage damaging diseases such as RA or osteoarthritis.

Full Text

The Full Text of this article is available as a PDF (467K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • van Holten Judith, Plater-Zyberk Christine, Tak Paul P. Interferon-beta for treatment of rheumatoid arthritis? Arthritis Res. 2002;4(6):346–352. [PMC free article] [PubMed]
  • Martel-Pelletier J, Alaaeddine N, Pelletier JP. Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci. 1999 Oct 15;4:D694–D703. [PubMed]
  • Lotz M, Blanco FJ, von Kempis J, Dudler J, Maier R, Villiger PM, Geng Y. Cytokine regulation of chondrocyte functions. J Rheumatol Suppl. 1995 Feb;43:104–108. [PubMed]
  • Fernandes J, Tardif G, Martel-Pelletier J, Lascau-Coman V, Dupuis M, Moldovan F, Sheppard M, Krishnan BR, Pelletier JP. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol. 1999 Apr;154(4):1159–1169. [PMC free article] [PubMed]
  • Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem. 1991 Jun 5;266(16):10331–10336. [PubMed]
  • Granowitz EV, Clark BD, Mancilla J, Dinarello CA. Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem. 1991 Aug 5;266(22):14147–14150. [PubMed]
  • Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55. [PubMed]
  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. [PubMed]
  • Haskill S, Martin G, Van Le L, Morris J, Peace A, Bigler CF, Jaffe GJ, Hammerberg C, Sporn SA, Fong S, et al. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. [PMC free article] [PubMed]
  • Muzio M, Polentarutti N, Sironi M, Poli G, De Gioia L, Introna M, Mantovani A, Colotta F. Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. J Exp Med. 1995 Aug 1;182(2):623–628. [PMC free article] [PubMed]
  • Malyak M, Guthridge JM, Hance KR, Dower SK, Freed JH, Arend WP. Characterization of a low molecular weight isoform of IL-1 receptor antagonist. J Immunol. 1998 Aug 15;161(4):1997–2003. [PubMed]
  • Coclet-Ninin J, Dayer JM, Burger D. Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells. Eur Cytokine Netw. 1997 Dec;8(4):345–349. [PubMed]
  • Sciacca FL, Canal N, Grimaldi LM. Induction of IL-1 receptor antagonist by interferon beta: implication for the treatment of multiple sclerosis. J Neurovirol. 2000 May;6 (Suppl 2):S33–S37. [PubMed]
  • Liu JS, Amaral TD, Brosnan CF, Lee SC. IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia. J Immunol. 1998 Aug 15;161(4):1989–1996. [PubMed]
  • Hattori T, Kubota S, Yutani Y, Fujisawa T, Nakanishi T, Takahashi K, Takigawa M. Change in cellular localization of a rheumatoid arthritis-related antigen (RA-A47) with downregulation upon stimulation by inflammatory cytokines in chondrocytes. J Cell Physiol. 2001 Feb;186(2):268–281. [PubMed]
  • Smeets TJ, Dayer JM, Kraan MC, Versendaal J, Chicheportiche R, Breedveld FC, Tak PP. The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis. Arthritis Rheum. 2000 Feb;43(2):270–274. [PubMed]
  • Lotz M, Clark-Lewis I, Ganu V. HIV-1 transactivator protein Tat induces proliferation and TGF beta expression in human articular chondrocytes. J Cell Biol. 1994 Feb;124(3):365–371. [PMC free article] [PubMed]
  • Klareskog L, Forsum U, Malmnäs Tjernlund UK, Kabelitz D, Wigren A. Appearance of anti-HLA-DR-reactive cells in normal and rheumatoid synovial tissue. Scand J Immunol. 1981 Aug;14(2):183–192. [PubMed]
  • Gabay C, Smith MF, Eidlen D, Arend WP. Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. J Clin Invest. 1997 Jun 15;99(12):2930–2940. [PMC free article] [PubMed]
  • Oritani K, Kincade PW, Zhang C, Tomiyama Y, Matsuzawa Y. Type I interferons and limitin: a comparison of structures, receptors, and functions. Cytokine Growth Factor Rev. 2001 Dec;12(4):337–348. [PubMed]
  • Palmer Gaby, Guerne Pierre-Andre, Mezin Francoise, Maret Michel, Guicheux Jerome, Goldring Mary B, Gabay Cem. Production of interleukin-1 receptor antagonist by human articular chondrocytes. Arthritis Res. 2002;4(3):226–231. [PMC free article] [PubMed]
  • Nicoletti F, Patti F, DiMarco R, Zaccone P, Nicoletti A, Meroni P, Reggio A. Circulating serum levels of IL-1ra in patients with relapsing remitting multiple sclerosis are normal during remission phases but significantly increased either during exacerbations or in response to IFN-beta treatment. Cytokine. 1996 May;8(5):395–400. [PubMed]
  • Perini P, Tiberio M, Sivieri S, Facchinetti A, Biasi G, Gallo P. Interleukin-1 receptor antagonist, soluble tumor necrosis factor-alpha receptor type I and II, and soluble E-selectin serum levels in multiple sclerosis patients receiving weekly intramuscular injections of interferon-beta1a. Eur Cytokine Netw. 2000 Mar;11(1):81–86. [PubMed]
  • Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001 May;2(5):378–386. [PubMed]
  • Muzio M, Polentarutti N, Facchetti F, Peri G, Doni A, Sironi M, Transidico P, Salmona M, Introna M, Mantovani A. Characterization of type II intracellular IL-1 receptor antagonist (IL-1ra3): a depot IL-1ra. Eur J Immunol. 1999 Mar;29(3):781–788. [PubMed]
  • Watson JM, Lofquist AK, Rinehart CA, Olsen JC, Makarov SS, Kaufman DG, Haskill JS. The intracellular IL-1 receptor antagonist alters IL-1-inducible gene expression without blocking exogenous signaling by IL-1 beta. J Immunol. 1995 Nov 1;155(9):4467–4475. [PubMed]
  • Palmer Gaby, Talabot-Ayer Dominique, Szalay-Quinodoz Ildiko, Maret Michel, Arend William P, Gabay Cem. Mice transgenic for intracellular interleukin-1 receptor antagonist type 1 are protected from collagen-induced arthritis. Eur J Immunol. 2003 Feb;33(2):434–440. [PubMed]
  • Chabaud M, Page G, Miossec P. Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage inflammatory protein-3alpha production in rheumatoid arthritis: regulation by soluble receptors and Th2 cytokines. J Immunol. 2001 Nov 15;167(10):6015–6020. [PubMed]
  • van de Loo Fons A J, van den Berg Wim B. Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators. Rheum Dis Clin North Am. 2002 Feb;28(1):127–149. [PubMed]
  • Tak PP, Hart BA, Kraan MC, Jonker M, Smeets TJ, Breedveld FC. The effects of interferon beta treatment on arthritis. Rheumatology (Oxford) 1999 Apr;38(4):362–369. [PubMed]

Figures and Tables

Figure 1
Expression of IFNAR1 and IFNAR2 mRNA in human articular chondrocytes and synovial fibroblasts. Expression of mRNA encoding (A) IFNAR1 and (B) IFNAR2 was assessed by RT-PCR using total RNA from freshly isolated (lanes 1, 6, 7) or dedifferentiated (passage ...
Figure 2
Dose dependent effects of IFNß and IL1ß on IL1Ra secretion by human articular chondrocytes. (A) Human articular chondrocytes freshly isolated from OA knee joint cartilage or (B) dedifferentiated human articular chondrocytes (passage 4, ...
Figure 3
Effects of IFNß and IL1ß on the production of secreted and intracellular IL1Ra by in human articular chondrocytes. (A) Human articular chondrocytes freshly isolated from normal adult femoral head cartilage or (B) dedifferentiated human ...
Figure 4
Effects of IFNß and IL1ß on the expression of sIL1Ra mRNA in human articular chondrocytes. Expression of mRNA encoding sIL1Ra was quantified by real time RT-PCR using total RNA from dedifferentiated human articular chondrocytes (passages ...
Figure 5
Dose dependent effects of IFNß and IL1ß on IL1Ra production in human synovial fibroblasts. (A) Human OA synovial fibroblasts (passage 4) were left unstimulated (control; white bars) or stimulated with indicated doses of IFNß (grey ...
Figure 6
Effects of IFNß and IL1ß on the production of secreted and intracellular IL1Ra in human synovial fibroblasts. Human RA synovial fibroblasts (passage 5) were left unstimulated (control; white bars) or stimulated with 2500 U/ml (10 ng/ml) ...
Figure 7
Effects of IFNß and IL1ß on the expression of sIL1Ra and icIL1Ra1 mRNA in human synovial fibroblasts. Expression levels of mRNA encoding (A) sIL1Ra and (B) icIL1Ra1 were quantified by real time RT-PCR using total RNA from human synovial ...

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...