title: Therapeutic effects of acetylsalicylic acid in giant cell arteritis.
abstract: OBJECTIVE
  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.
  
  
  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 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).
  
  
  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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. weyand.cornelia@mayo.edu
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.forename: Hongyu
authors.initials: H
authors.lastname: Yang
authors.forename: Brian
authors.initials: B
authors.lastname: Younge
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D013700:Giant Cell Arteritis / Q000188:drug therapy* / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013699:Temporal Arteries / Q000637:transplantation; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D007371:Interferon-gamma; D001241:Aspirin; D007213:Indomethacin