Volume 5 Supplement 3

3rd World Congress of the Global Arthritis Research Network (GARN): International Arthritis Summit

Open Access

IL-15 and its role in rheumatoid arthritis

  • M Kurowska-Stolarska1,
  • O Distler1,
  • W Rudnicka2,
  • J Distler1,
  • RE Gay1,
  • W Maslinski2 and
  • S Gay1
Arthritis Res Ther20035(Suppl 3):139

https://doi.org/10.1186/ar940

Published: 12 September 2003

Background

IL-15 is involved in all phases of rheumatoid arthritis. Recently we have shown that rheumatoid arthritis synovial fibroblasts (RASF) express both IL-15 and functional IL-15 receptor [1].

Objective

The aim of present study was to identify pathways that are regulated by autocrine IL-15 (IL-15R) in RASF.

Methods

RASF were transfected with plasmid encoding IL-15R antagonist (CRB-15, Cardion AG) or control constructs. RNA from transient transfectants were used for Microarray analysis. The differential expression of genes obtained by microarray analysis was verified by SYBR Green real-time PCR. The expression of IL-15Rα, cell proliferation and the expression of p16 and p21 were evaluated in stably transfected cells.

Results

The IL-15R antagonist produced by transfected RASF blocked the endogenous IL-15/IL-15Rα interaction, which resulted in an inhibition of cell proliferation (45 ± 10%) via an increase of the expression of p16. In addition, we found that inhibition of IL-15Rα induced the expression of mRNA for FGFR-3. Since two isoforms of FGFR-3 have been identified (FGFR-3b and FGFR-3c) [2], we tested the effect of IL-15Rα inhibition on their expression. In contrast to FGFR-3b, the level of mRNA for FGFR-3c was strongly increased in cells transfected with the IL-15R antagonist (4.71 ± 2.5 in transient transfectants and 6.1 ± 1 fold in stable transfectants). FGFR-3c isoform binds specifically FGF-9, but also FGF-2 [2]. Besides FGFR-3, FGF-2 that is abundant in RA joints binds to FGFR-1. In vitro studies revealed that FGFR-1 transmits a potent mitogenic signal, whereas FGFR-3 usually has no stimulatory effect or inhibits cell proliferation. In contrast to FGFR-3c, blocking of IL-15Rα did not change the mRNA expression for FGFR-1 in RASF. Moreover, we checked whether FGF-2 affects the expression of IL-15Rα. Indeed, FGF-2 strongly decreased the spontaneous and tumor necrosis factor alpha-triggered expression of IL-15Rα at the mRNA and protein levels.

Conclusion

Our findings raise the possibility of a negative loop between FGF-2/FGFR-3c and IL-15/IL-15R signaling in RASF. Moreover, the activation of RASF by FGFs could depend on the ratio of FGFR-1/FGFR-3 expression, which is controlled by the endogenous IL-15/IL-15R system.

Authors’ Affiliations

(1)
Center of Experimental Rheumatology, University Hospital
(2)
Department of Pathophysiology and Immunology, Institute of Rheumatology

References

  1. Kurowska M, et al: J Immunol. 2002, 169: 1760-View ArticlePubMedGoogle Scholar
  2. Powers CJ, et al: Endocr Relat Cancer. 2000, 7: 165-10.1677/erc.0.0070165.View ArticlePubMedGoogle Scholar

Copyright

© BioMed Central Ltd 2003

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