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Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-x_L and Bcl-2¹

Mariola Kurowska^*, Weronika Rudnicka^*, Ewa Kontny^*, Iwona Janicka^*, Magdalena Chorazy^*, Jacek Kowalczewski, Maria Ziókowska^*, Sylvie Ferrari-Lacraz^2,, Terry B. Strom and Wodzimierz Maliski^3,*,

^* Department of Pathophysiology and Immunology, and Clinic of Orthopaedy, Institute of Rheumatology, Warsaw, Poland; Division of Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Department of Experimental and Clinical Physiology, Medical University of Warsaw, Warsaw, Poland

The hallmarks of rheumatoid arthritis (RA) are leukocytic infiltration of the synovium and expansiveness of fibroblast-like synoviocytes (FLS). The abnormal proliferation of FLS and their resistance to apoptosis is mediated, at least in part, by present in RA joints proinflammatory cytokines and growth factors. Because IL-15 exerts properties of antiapoptotic and growth factors, and is produced by RA FLS, we hypothesized that IL-15 participates in RA FLS activation. To test this hypothesis, we first examined whether RA FLS express chains required for high affinity functional IL-15R. Indeed, RA FLS express IL-15R at mRNA and protein levels. Moreover, we confirmed the presence of IL-2R and common -chains. Interestingly, TNF- or IL-1 triggered significant elevation of IL-15R chain at mRNA and protein levels. Next, we investigated the effects of exogenous or endogenous IL-15 on Bcl-2 and Bcl-x_L expression, FLS proliferation, and apoptosis. Exogenous IL-15 enhanced RA FLS proliferation and increased the level of mRNA-encoding Bcl-x_L. To test the role of endogenous IL-15 in the activation of RA FLS, an IL-15 mutant/Fc2a protein exerting properties of specific antagonist to the IL-15R chain was used. We found that blocking IL-15 biological activities using this protein substantially reduced endogenous expression of Bcl-2 and Bcl-x_L, and RA FLS proliferation that was reflected by increased apoptosis. Thus, we have demonstrated that a distinctive phenotype of RA FLS, i.e., persistent activation, proliferation, and resistance to apoptosis, is related to the autocrine activation of IL-15Rs by FLS-derived IL-15.

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