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The Journal of Immunology, 2000, 165: 4718-4724.
Copyright © 2000 by The American Association of Immunologists

Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis1

Catherine M. Greene, Gerard Meachery, Clifford C. Taggart, Cyril P. Rooney, Raymond Coakley, Shane J. O’Neill and Noel G. McElvaney2

Department of Respiratory Research, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland

Sarcoidosis is a granulomatous disease of unknown etiology associated with the expansion of IL-2-producing activated CD4+ T lymphocytes. A number of factors including the recently described IL-18 have been implicated in IL-2 expression in vitro. We investigated the role of IL-18 in IL-2 expression in sarcoidosis. Eighteen individuals with sarcoidosis and 15 normal controls were studied. IL-18R expression and epithelial lining fluid (ELF) concentrations of IL-18 were significantly elevated in the sarcoid group (p = 0.0143 and 0.0024, respectively). Both AP1 and NF-{kappa}B, transcription factors that regulate IL-2 gene expression, were activated in vivo in sarcoid pulmonary CD4+ T lymphocytes. Transcription factor activity was not detected in pulmonary CD4+ T lymphocytes from normal controls or from peripheral blood CD4+ T lymphocytes from individuals with sarcoidosis, further evidence of compartmentalization of the lymphoproliferative process in this condition. We examined the effects of IL-18 on AP1 and NF-{kappa}B in Jurkat T cells in vitro. These effects were both time and dose dependent. Examination of transcription factor activation and IL-2 gene expression in Jurkat T cells revealed that sarcoid but not normal ELF activated AP1 and NF-{kappa}B, induced IL-2 gene transcription, and up-regulated IL-2 protein production. Addition of IL-18 to normal ELF also induced IL-2 mRNA accumulation, whereas correspondent depletion of IL-18 from sarcoid ELF using neutralizing Abs abrogated all of the effects. These data strongly implicate IL-18 in the pathogenesis of sarcoidosis via activation of AP1 and NF-{kappa}B, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.




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