Interleukin-4 suppression of tumor necrosis factor α-stimulated E- selectin gene transcription is mediated by STAT6 antagonism of NF-κB

Abstract

Interleukin-4 (IL-4), an immunoregulatory cytokine secreted from activated T-helper 2 lymphocytes, eosinophils, and mast cells, stimulates the expression of a number of immune system genes via activation of the transcription factor, STAT6. However, IL-4 can concomitantly suppress the expression of other immune-related gene products, including κ light chain, FcγRI, IL-8, and E-selectin. We demonstrate that IL-4 activates STAT6 in human vascular endothelial cells and that two STAT6 binding sites are present in the promoter of the E-selectin gene. IL-4-induced STAT6 binding does not activate E-selectin transcription but instead suppresses tumor necrosis factor α-induced expression of the E-selectin gene. STAT6 was found to compete for binding to a region in the E-selectin gene promoter containing overlapping STAT6 and NF-κB binding sites, effectively acting as an antagonist of NF-κB binding and transcriptional activation. This novel mechanism for IL-4-mediated inhibition of inflammatory gene expression provides an example of a STAT factor acting as a transcriptional repressor rather than an activator.