Temporal Transcriptional Regulation of IL-10-Induced Anti-Inflammatory Genes in LPS-Triggered Macrophages
Interleukin-10 (IL-10) is an important anti-inflammatory cytokine acting to dampen macrophage activation during and after the immune response to microbial pathogens. During the innate immune response to gram-negative bacteria, macrophages are triggered to produce numerous pro-inflammatory mediators through Toll-like receptor 4 (TLR4) binding to lipopolysaccharide (LPS). IL-10 acts on these cells through the induced expression of genes that inhibit expression of select TLR-induced pro-inflammatory genes. Our understanding of the mechanisms by which cells respond to IL-10 with the anti-inflammatory response remains incomplete. Herein, I investigated the IL-10-induced transcriptional response that occurs in TLR-activated macrophages. I analyzed the kinetic profile of expression for a group of genes induced by IL-10 in a manner that depends on synergy with TLR signaling (referred to as IL-10 super-induced genes). IL-10 induces the expression of these target genes in three distinct temporal waves - first, primary response genes, followed by early secondary response genes, and then late secondary response genes. All of the IL-10 super-induced genes appear to be expressed through an increase in their transcription rate. Thus, the IL-10 anti-inflammatory response in macrophages involves specific crosstalk between IL-10 and TLR signaling leading to a transcriptional cascade of distinct waves of anti-inflammatory gene expression.
innate immunity, toll-like receptor, LPS, IL-10, macrophages, inflammation, cytokines, transcription, signal transduction, signaling crosstalk, Biology
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