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

• Published in: The Journal of immunology (1950) Vol. 165; no. 8; pp. 4718 - 4724
• Main Authors: Greene, Catherine M, Meachery, Gerard, Taggart, Clifford C, Rooney, Cyril P, Coakley, Raymond, O'Neill, Shane J, McElvaney, Noel G
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.10.2000
• Subjects: Adult; Bronchoalveolar Lavage Fluid - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cytokines - metabolism; Epithelium - immunology; Epithelium - metabolism; Female; Gene Expression Regulation - immunology; Humans; Interleukin-18 - metabolism; Interleukin-18 - physiology; Interleukin-18 Receptor alpha Subunit; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Jurkat Cells - immunology; Jurkat Cells - metabolism; Lymphocyte Activation - immunology; Male; Middle Aged; NF-kappa B - metabolism; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - blood; Receptors, Interleukin-18; Sarcoidosis, Pulmonary - immunology; Sarcoidosis, Pulmonary - metabolism; Sarcoidosis, Pulmonary - pathology; Th1 Cells - immunology; Th1 Cells - metabolism; Transcription Factor AP-1 - blood; Transcription Factor AP-1 - metabolism; Transcriptional Activation - immunology; U937 Cells
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.8.4718

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.