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 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.
Greene
C M
CM
Department of Respiratory Research, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Meachery
G
G
Taggart
C C
CC
Rooney
C P
CP
Coakley
R
R
O'Neill
S J
SJ
McElvaney
N G
NG
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000097:blood; D053724:Receptors, Interleukin-18; D017565:Sarcoidosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000097:blood / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D020298:U937 Cells
D016207:Cytokines; C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D007376:Interleukin-2; D016328:NF-kappa B; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018808:Transcription Factor AP-1