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

      The Journal of Immunology Author Choice
      Adult, Bronchoalveolar Lavage Fluid, immunology, CD4-Positive T-Lymphocytes, metabolism, pathology, Cytokines, Epithelium, Female, Gene Expression Regulation, Humans, Interleukin-18, physiology, Interleukin-18 Receptor alpha Subunit, Interleukin-2, biosynthesis, genetics, Jurkat Cells, Lymphocyte Activation, Male, Middle Aged, NF-kappa B, Receptors, Interleukin, blood, Receptors, Interleukin-18, Sarcoidosis, Pulmonary, Th1 Cells, Transcription Factor AP-1, Transcriptional Activation, U937 Cells

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          Abstract

          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-kappaB, 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-kappaB 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-kappaB, 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-kappaB, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.

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