Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves' disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor.
We have reported recently that IgG from patients with Graves' disease (GD) can induce the expression of the CD4-specific T lymphocyte chemoattractant, IL-16, and RANTES, a C-C chemokine, in their fibroblasts. This induction is mediated through the insulin-like growth factor-1 receptor (IGF-1R) pathway. We now report that Abs from individuals with active rheumatoid arthritis (RA-IgG) stimulate in their synovial fibroblasts the expression of these same cytokines. IgG from individuals without known autoimmune disease fails to elicit this chemoattractant production. Furthermore, RA-IgG fails to induce IL-16 or RANTES expression in synovial fibroblasts from donors with osteoarthritis. RA-IgG-provoked IL-16 and RANTES production also appears to involve the IGF-1R because receptor-blocking Abs prevent the response. RA fibroblasts transfected with a dominant-negative mutant IGF-1R fail to respond to RA-IgG. IGF-1 and the IGF-1R-specific analog Des(1-3) also induce cytokine production in RA fibroblasts. RA-IgG-provoked IL-16 expression is inhibited by rapamycin, a specific macrolide inhibitor of the Akt/FRAP/mammalian target of rapamycin/p70(s6k) pathway, and by dexamethasone. GD-IgG can also induce IL-16 in RA fibroblasts, and RA-IgG shows similar activity in GD fibroblasts. Thus, IgGs from patients with RA, like those associated with GD, activate IGF-1R, and in so doing provoke T cell chemoattraction expression in fibroblasts, suggesting a potential common pathway in the two diseases. Immune-competent cell trafficking to synovial tissue is integral to the pathogenesis of RA. Recognition of this novel RA-IgG/fibroblast interaction and its functional consequences may help identify therapeutic targets.
Pritchard
Jane
J
Division of Molecular Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90502, USA.
Tsui
Shanli
S
Horst
Noah
N
Cruikshank
William W
WW
Smith
Terry J
TJ
D000906:Antibodies / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000378:metabolism; D002630:Chemotactic Factors / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019410:Interleukin-16 / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D018946:Chemokine CCL5; D002630:Chemotactic Factors; D007166:Immunosuppressive Agents; D019410:Interleukin-16; D017451:Receptors, Somatomedin; D020123:Sirolimus