Activation Of Epidermal Growth Factor Receptor In Macrophage Regulates Cytokine Production And Experimental Colitis

BACKGROUND&AIMS:Macrophages regulate innate immune response to maintain intestinal homeostasis and play a pathological role in intestinal inflammation. Epidermal growth factor (EGF) signaling is well known for promoting cell growth. However, the impact of EGF signaling in macrophages remains unclear. This study was to determine the role and mechanism of EGF signaling in macrophages in cytokine production and intestinal inflammation. METHODS: Cytokine production and signaling pathways in macrophages with EGF receptor (EGFR) kinase inactive mutation or pharmacological inhibition were studied in vitro. Lipopolysaccharide (LPS)-stimulated cytokine production and dextran sulfate sodium (DSS)-induced intestinal injury and inflammation were investigated using Egfr fl/fl LysM-Cre mice with EGFR deleted in macrophages. RESULTS:LPS stimulated EGFR activation and blocking EGFR kinase activity increased LPS and interferon (IFN)-y-stimulated tumor necrosis factor (TNF) and interleukin (IL)-10production, which correlated with increasing p38and NF-κB activation in mouse peritoneal macrophages and in mouse macrophage RAW264.7cell line. LPS-stimulated TNF and IL-10production was enhanced in Egfr fl/fl LysM-Cre mice, compared to those in LysM-Cre mice. EGFR was activated in colonic macrophages in patients with ulcerative colitis and in mice with DSS-induced colitis. Compared to LysM-Cre mice treated with DSS, acute colitis was ameliorated, recovery from colitis was promoted, and IL-10level was persistently increased in acute colitis and recovery phase, however, TNF was increased in acute colitis, but decreased in the recovery phase in Egfrfl/fl LysM-Cre mice. Anti-IL-10neutralizing antibody abolished these effects on Egfrfl/fl LysM-Cre mice, which suggests that increased IL-10blocks TNF production and protects mice from colitis in Egfrfl/flLysM-Cre mice. CONCLUSIONS:These results provide a novel finding that deletion of EGFR increases both pro-and anti-inflammatory cytokine production in macrophages, and increased IL-10production leads to suppressing pro-inflammatory cytokine production, resulting in protecting mice from intestinal inflammation.