IL-15 and its role in rheumatoid arthritis

Kurowska-Stolarska, M. , Distler, O., Rudnicka, W., Distler, J., Gay, R.E., Maslinski, W. and Gay, S. (2003) IL-15 and its role in rheumatoid arthritis. In: 3rd World Congress of the Global Arthritis Research Network (GARN): International Arthritis Summit, Miyakazi, Japan, 14-17 Sept 2003, p. 139. (doi:10.1186/ar940)

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Abstract

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.

Item Type:Conference Proceedings
Additional Information:Special Issue: Arthritis Research and Therapy, 5(Sup 3):139
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kurowska-Stolarska, Dr Mariola
Authors: Kurowska-Stolarska, M., Distler, O., Rudnicka, W., Distler, J., Gay, R.E., Maslinski, W., and Gay, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arthritis Research and Therapy
Publisher:BioMed Central
ISSN:1465-9905
ISSN (Online):1465-9905

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