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Synoviocyte Stimulation by the LFA-1–Intercellular Adhesion Molecule-2–Ezrin–Akt Pathway in Rheumatoid Arthritis¹

Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322

In rheumatoid arthritis (RA), the synovium is infiltrated by mononuclear cells that influence the proliferation and activation of fibroblast-like synoviocytes (FLS) through soluble mediators as well as cell-to-cell contact. To identify receptor-ligand pairs involved in this cross-talk, we cocultured T cells with FLS lines isolated from synovial tissues from RA patients. Coculture with T cells induced phosphorylation of Akt (Ser⁴⁷³) and its downstream mediators, GSK-3/GSK-β, FoxO1/3a, and mouse double minute-2, and enhanced FLS proliferation. T cell-mediated phospho-Akt up-regulation was unique for FLS as no such effect was observed upon interaction of T cells with dendritic cells and B cells. Akt activation was induced by all functional T cell subsets independent of MHC/Ag recognition and was also found with other leukocyte populations, suggesting the involvement of a common leukocyte cell surface molecule. Akt phosphorylation, enhanced in vitro FLS proliferation, and enhanced FLS IL-6 production was inhibited by blocking Abs to CD11a and ICAM-2 whereas Abs to ICAM-1 had a lesser effect. Selective involvement of the LFA-1–ICAM-2 pathway was confirmed by the finding of increased ezrin phosphorylation at Tyr³⁵³ that is known to be downstream of ICAM-2 and supports cell survival through Akt activation. CD28^– T cells, which are overrepresented in RA patients, have high CD11a cell surface expression and induce Akt phosphorylation in FLS more potently than their CD28⁺ counterparts. These findings identify ICAM-2 as a potential therapeutic target to inhibit FLS activation in RA, allowing for a more selective intervention than broad LFA-1 inhibition.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Institutes of Health (RO1 AR 41974, RO1 AI 44142, and RO1 AR 42527).

² Address correspondence and reprint requests to Dr. Jörg J. Goronzy, Lowance Center for Human Immunology, School of Medicine, Emory University, 101 Woodruff Circle No. 1003, Atlanta, GA 30322. E-mail address: jgoronz{at}emory.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; FLS, fibroblast-like synoviocyte; PTEN, phosphatase and tensin homolog; MDM-2, mouse double minute-2.