Glucocorticoid-mediated repression of cytokine gene transcription in human arteritis-SCID chimeras

Alexander Brack, Heike L. Rittner, Brian R. Younge, Christian Kaltschmidt, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Giant cell arteritis (GCA) is a vasculitic syndrome that preferentially affects medium and large-sized arteries. Glucocorticoid therapy resolves clinical symptoms within hours to days, but therapy has to be continued over several years to prevent disease relapses. It is not known whether and how glucocorticoids affect the function of the inflammatory infiltrate or why the disease persists subclinically despite chronic treatment. GCA is self- sustained in temporal arteries engrafted into SCID mice, providing a model in which the mechanisms of action and limitations of glucocorticoid therapy can be examined in vivo. Administration of dexamethasone to temporal artery-SCID chimeras for 1 wk induced a partial suppression of T cell and macrophage function as indicated by the reduced tissue concentrations of IL-2, IL-1β, and IL-6 mRNA, and by the diminished expression of inducible NO synthase. In contrast, synthesis of IFN-γ, mRNA was only slightly decreased, and expression of TGF-β1 was unaffected. These findings correlated with activation of the IκBα gene and blockade of the nuclear translocation of NFκB in the xenotransplanted tissue. Dose-response experiments suggested that steroid doses currently used in clinical medicine are suboptimal in repressing NFκB-mediated cytokine production in the inflammatory lesions. Chronic steroid therapy was able to deplete the T cell products IL-2 and IFN- γ, whereas the activation of tissue-infiltrating macrophages was only partially affected. IL-1β transcription was abrogated; in contrast, TGF-β1 mRNA synthesis was steroid resistant. The persistence of TGF-β1-transcribing macrophages, despite paralysis of T cell function, may provide an explanation for the chronicity of the disease, and may identify a novel therapeutic target in this inflammatory vasculopathy.

Original languageEnglish (US)
Pages (from-to)2842-2850
Number of pages9
JournalJournal of Clinical Investigation
Volume99
Issue number12
DOIs
StatePublished - Jun 15 1997

Keywords

  • Giant cell arteritis
  • NFκB
  • SCID mouse
  • TGF-β
  • Vasculitis

ASJC Scopus subject areas

  • Medicine(all)

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