Resolvin D1 downregulates IL-6-induced Monocyte Chemoattractant Protein-1 production through suppression of JAK2-STAT3 signaling

Abstract

Chronic inflammation is considered to increase the risk for developing a majority of human malignancies including colorectal cancer. During inflammation, the influx of macrophages increases, which may contribute to cancer-prone microenvironment. Interleukin 6 (IL-6), a pro-inflammatory cytokine, is considered to stimulate macrophage infiltration into the inflamed site via the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) signal transduction axis. Hence, IL-6 is a major linker of chronic inflammation and cancer. Resolvin D1 (RvD1), an endogenous lipid mediator generated from docosahexaenoic acid, is known to promote resolution of inflammation, and is speculated to prevent chronic inflammation-induced carcinogenesis. In the present study, we found that the infiltration of macrophage-like U937 cells was stimulated when co-cultured with intestinal epithelial CCD841CoN cells in the presence of IL-6. However, RvD1 abrogated the IL-6-induced macrophage infiltration which was associated with suppression of IL-6-induced monocyte chemoattractant protein-1 (MCP-1) production. MCP-1 is thought to be the most important chemokine for recruitment of macrophages during chronic inflammation. Knockdown of STAT3 abolished IL-6-induced MCP-1 production as well as macrophage infiltration. Through interaction with IL-6 receptor, RvD1 interfered with binding of IL-6 to its receptor, resulting in suppression of JAK2-STAT3 signaling. Besides acting as an IL-6 antagonist, RvD1 downregulated the interaction between gp130 and IL-6 receptor through formyl peptide receptor 2 (FPR2/ALX). Taken together, these findings suggest that RvD1 attenuates IL-6-induced MCP-1 production through inhibition of JAK2-STAT3 signaling, thereby preventing inflammation-induced macrophage infiltration.