Therapeutic effects of acetylsalicylic acid in giant cell arteritis

Objective In giant cell arteritis (GCA), inflammatory lesions typically produce interferon‐γ (IFNγ)– and nuclear factor κB (NF‐κB)–dependent monokines. Corticosteroids influence disease activity by repressing NF‐κB–dependent genes but have only marginal effects on IFNγ. The current study explored whether acetylsalicylic acid (ASA) had cytokine‐repressing activity in GCA and could function as a steroid‐sparing agent. Methods 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 IFNγ and interleukin‐1β (IL‐1β) 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‐κB and activator protein 1 (AP‐1) were assessed by electrophoretic mobility shift assays (EMSAs). Results 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‐κB–regulated monokines, ASA acted predominantly by suppressing IFNγ. Indomethacin failed to reduce tissue IFNγ transcription, which therefore excluded the inhibition of cyclooxygenases as a critical mechanism. IFNγ production by T cell clones was highly sensitive to ASA‐mediated suppression, whereas IL‐1β 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‐κB. Conclusion 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.