Therapeutic effects of acetylsalicylic acid in giant cell arteritis ARTHRITIS AND RHEUMATISM Weyand, C. M., Kaiser, M., Yang, H. Y., Younge, B., Goronzy, J. J. 2002; 46 (2): 457-466

Abstract

In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-gamma(IFNgamma)-- and nuclear factor kappaB (NF-kappaB)-dependent monokines. Corticosteroids influence disease activity by repressing NF-kappaB-dependent genes but have only marginal effects on IFNgamma. The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent.Temporal artery-severe combined immunodeficiency (SCID) mouse chimeras were created by engrafting inflamed temporal arteries into SCID mice. Chimeras were treated with ASA, indomethacin, or dexamethasone for 3 weeks. Temporal artery grafts were harvested and cytokine message was semiquantified by polymerase chain reaction-enzyme-linked immunosorbent assay. The ability of dexamethasone and ASA to suppress IFNgamma and interleukin-1beta (IL-1beta) messenger RNA and protein production was also tested in vitro using T cell clones and monocytes derived from patients with GCA. Drug-induced effects on the transcription factors NF-kappaB and activator protein 1 (AP-1) were assessed by electrophoretic mobility shift assays (EMSAs).At clinically relevant doses, 20-100 mg/kg, ASA was a highly effective inhibitor of cytokine transcription in temporal arteries. While dexamethasone preferentially targeted NF-kappaB-regulated monokines, ASA acted predominantly by suppressing IFNgamma. Indomethacin failed to reduce tissue IFNgamma transcription, which therefore excluded the inhibition of cyclooxygenases as a critical mechanism. IFNgamma production by T cell clones was highly sensitive to ASA-mediated suppression, whereas IL-1beta production by lipopolysaccharide-stimulated monocytes responded primarily to dexamethasone. The combination of ASA and dexamethasone had synergistic effects. EMSAs demonstrated that ASA interfered with the formation of AP-1, whereas dexamethasone suppressed the nuclear translocation of NF-kappaB.The results of this study provide evidence of the complementary action of ASA and corticosteroids in suppressing proinflammatory cytokines in the vascular lesions of GCA.

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View details for PubMedID 11840449