Inhibition of Inflammatory Gene Transcription by IL-10 Is Associated with Rapid Suppression of Lipopolysaccharide-Induced Enhancer Activation

Author(s)

Conaway, Evan A. ; de Oliveira, Dalila C. ; McInnis, Christine M. ; Snapper, Scott B. ; Horwitz, Bruce H.

• Document type: Journal article
• Source: JOURNAL OF IMMUNOLOGY; v. 198, n. 7, p. 2906-2915, APR 1 2017.
• Web of Science Citations: 9

Abstract

IL-10 limits the magnitude of inflammatory gene expression following microbial stimuli and is essential to prevent inflammatory disease; however, the molecular basis for IL-10-mediated inhibition remains elusive. Using a genome-wide approach, we demonstrate that inhibition of transcription is the primary mechanism for IL-10-mediated suppression in LPS-stimulated macrophages and that inhibited genes can be divided into two clusters. Genes in the first cluster are inhibited only if IL-10 is included early in the course of LPS stimulation and is strongly enriched for IFN-inducible genes. Genes in the second cluster can be rapidly suppressed by IL-10 even after transcription is initiated, and this is associated with suppression of LPS-induced enhancer activation. Interestingly, the ability of IL-10 to rapidly suppress active transcription exhibits a delay following LPS stimulation. Thus, a key pathway for IL-10-mediated suppression involves rapid inhibition of enhancer function during the secondary phase of the response to LPS. (AU)

• FAPESP's process: 15/02610-6 - Evaluation of glutamine as modulator of the transcription factor NF-kB and c-Rel in macrophages and lymphocytes from IL-10 knock out mice subjected to dietary restriction
• Grantee: Dalila Cunha de Oliveira
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate