Role of IL-18 in CD4(+) T lymphocyte activation in sarcoidosis

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 contro ls were studied. IL-18R expression and epithelial lining fluid (ELF) concen trations of IL-18 were significantly elevated in the sarcoid group (p = 0.0 143 and 0.0024, respectively). Both AP1 and NF-kappa B, transcription facto rs that regulate IL-2 gene expression, were activated in vivo in sarcoid pu lmonary CD4(+) T lymphocytes, Transcription factor activity was not detecte d in pulmonary CD4(+) T lymphocytes from normal controls or from peripheral blood CD4(+) T lymphocytes from individuals with sarcoidosis, further evid ence of compartmentalization of the lymphoproliferative process in this con dition. 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, Examinatio n of transcription factor activation and IL-2 gene expression in Jurkat T c ells 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, where as correspondent depletion of IL-18 from sarcoid ELF using neutralizing Abs abrogated all of the effects. These data strongly implicate IL-18 in the p athogenesis of sarcoidosis via activation of API and NF-kappa B, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.