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Originally published In Press as doi:10.1074/jbc.M206337200 on July 8, 2002

J. Biol. Chem., Vol. 277, Issue 38, 34679-34691, September 20, 2002
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Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression*

Jacques C. M. MorelDagger §, Christy C. ParkDagger §, Kui ZhuDagger , Pawan KumarDagger , Jeffrey H. RuthDagger , and Alisa E. KochDagger ||

From the Dagger  Department of Medicine, Northwestern University Medical School and  Veterans Administration, Chicago Health Care System, Lakeside Division, Chicago, Illinois 60611

Vascular cell adhesion molecule (VCAM)-1 has been implicated in interactions between leukocytes and connective tissue, including rheumatoid arthritis (RA) synovial tissue fibroblasts. Such interactions within the synovium contribute to RA inflammation. Using phosphoinositide 3-kinase (PI3-kinase) inhibitor LY294002 and Src inhibitor PP2, we show that interleukin (IL)-18-induced ERK1/2 activation is Src kinase-dependent. Antisense (AS) c-Src oligonucleotide (ODN) treatment reduced IL-18-induced ERK1/2 expression by 32% compared with control, suggesting an upstream role of Src in ERK1/2 activation. AS c-Src ODN treatment also inhibited Akt expression by 74% compared with sense control. PI3-kinase inhibitor LY294002 or AS PI3-kinase ODN inhibited Akt expression. AS c-Src ODN inhibited Akt phosphorylation, confirming Src is upstream of PI3-kinase in IL-18-induced RA synovial fibroblast signaling. IL-18 induced a time-dependent activation of c-Src, Ras, and Raf-1, suggesting this signaling cascade plays a role in ERK activation. IL-18 directly activated Src kinase by more than 4-fold over basal levels by enzymatic assay. Electrophoretic mobility shift assay showed that activator protein-1 (AP-1) is activated by IL-18 through ERK and Src but not through PI3-kinase. In an alternate pathway, inhibition of IL-1 receptor-associated kinase-1 (IRAK) with AS ODN to IRAK reduced IL-18-induced expression of nuclear factor kappa B (NFkappa B). Finally, IL-18-induced cell surface VCAM-1 expression was inhibited by treatment with AS ODNs to c-Src, IRAK, PI3-kinase, and ERK1/2 by 57, 43, 41, and 32% compared with control sense ODN treatment, respectively. These data support a role for IL-18 activation of three distinct pathways during RA synovial fibroblast stimulation: two Src-dependent pathways and the IRAK/NFkappa B pathway. Targeting VCAM-1 signaling mechanisms may represent therapeutic approaches to inflammatory and angiogenic diseases characterized by adhesion molecule up-regulation.

* This work was supported by the Gallagher Professorship for Arthritis Research, funds from the Veterans Affairs Research Service, National Institutes of Health Grants AI-40987 (to A. E. K.), HL-58695 (to A. E. K.), and AI-49287-02 (to C. C. P.), and a grant from the French nonprofit organization Groupe d'Etudes et de Recherches Immuno-rhumatologiques (GERIR).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| To whom correspondence should be addressed: Dept. of Medicine, Division of Rheumatology, Northwestern University Medical School, 303 E. Chicago Ave., Ward 3-315, Chicago, IL 60611. Tel.: 312-503-1963; Fax: 312-503-0994; E-mail: ae-koch@northwestern.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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