GLUCOCORTICOID-MEDIATED REPRESSION OF CYTOKINE GENE-TRANSCRIPTION IN HUMAN ARTERITIS-SCID CHIMERAS

Giant cell arteritis (GCA) is a vasculitic syndrome that preferentiall y affects medium and large-sized arteries. Glucocorticoid therapy reso lves clinical symptoms within hours to days, but therapy has to be con tinued over several years to prevent disease relapses. It is not known whether and how glucocorticoids affect the function of the inflammato ry infiltrate or why the disease persists subclinically despite chroni c treatment. GCA is self-sustained in temporal arteries engrafted into SCID mice, providing a model in which the mechanisms of action and li mitations of glucocorticoid therapy can be examined in vivo. Administr ation of dexamethasone to temporal artery-SCID chimeras for 1 wk induc ed a partial suppression of T cell and macrophage function as indicate d by the reduced tissue concentrations of IL-2, IL-1 beta, and IL-6 mR NA, and by the diminished expression of inducible NO synthase. In cont rast, synthesis of IFN-gamma mRNA was only slightly decreased, and exp ression of TGF-beta 1 was unaffected. These findings correlated with a ctivation of the I kappa B alpha gene and blockade of the nuclear tran slocation of NF kappa B in the xenotransplanted tissue. Dose-response experiments suggested that steroid doses currently used in clinical me dicine are suboptimal in repressing NF kappa B-mediated cytokine produ ction in the inflammatory lesions. Chronic steroid therapy was able to deplete the T cell products IL-2 and IFN-gamma, whereas the activatio n of tissue-infiltrating macrophages was only partially affected. IL-1 beta transcription was abrogated; in contrast, TGF-beta 1 mRNA synthe sis was steroid resistant. The persistence of TGF-beta 1-transcribing macrophages, despite paralysis of T cell function, may provide an expl anation for the chronicity of the disease, and may identify a novel th erapeutic target in this inflammatory vasculopathy.