INTERLEUKIN-10 INHIBITS INTERFERON-GAMMA-INDUCED INTERCELLULAR-ADHESION MOLECULE-1 GENE-TRANSCRIPTION IN HUMAN MONOCYTES

Interleukin-10 (IL-10) is a potent monocyte regulatory cytokine that i nhibits gene expression of proinflammatory mediators, In this study, w e investigated the mechanism by which IL-10 downregulates expression o f intercellular adhesion molecule-1 (ICAM-1) on the cell surface of no rmal human monocytes activated with interferon-gamma (IFN-gamma). IL-1 0 inhibition of IFN-gamma-induced ICAM-1 expression was apparent as ea rly as 3 hours and was blocked by an anti-IL-10 antibody but not by an isotype-matched control antibody. Northern blot analysis showed that IL-10 reduced the accumulation of ICAM-1 mRNA in IFN-gamma-stimulated monocytes, IL-10 inhibition of ICAM-1 steady-state mRNA was detected a t 3 hours and remained at 24 hours, Nuclear run-on transcription assay s showed that IL-10 inhibited the rate of IFN-gamma-induced transcript ion of the ICAM-1 gene, and mRNA stability studies showed that IL-10 d id not alter the half-life of IFN-gamma-induced ICAM-1 message. Thus, IL-10 inhibits IFN-gamma-induced ICAM-1 expression in monocytes primar ily at the level of gene transcription. Activation of IFN-gamma-respon sive genes requires tyrosine phosphorylation of the transcriptional fa ctor STAT-1 alpha (signal transducer and activator of transcription-1 alpha). However, IL-10 did not affect IFN-gamma-induced tyrosine phosp horylation of STAT-1 alpha or alter STAT-1 alpha binding to the IFN-ga mma response element (IRE) in the ICAM-1 promoter. Instead, IL-10 prev ented IFN-gamma-induced binding activity at the NF-kappa B site of the tumor necrosis factor alpha (TNF-alpha)-responsive NF-kappa B/C-EBP c omposite element in the ICAM-1 promoter. These data indicate that IL-1 0 inhibits IFN-gamma-induced transcription of the ICAM-1 gene by a reg ulatory mechanism that may involve NF-kappa B. (C) 1997 by The America n Society of Hematology.