title: Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis.
abstract: Macrophages regulate innate immunity to maintain intestinal homeostasis and play pathological roles in intestinal inflammation. Activation of the epidermal growth factor receptor (EGFR) promotes cellular proliferation, differentiation, survival, and wound closure in several cell types. However, the impact of EGFR in macrophages remains unclear. This study was to investigate whether EGFR activation in macrophages regulates cytokine production and intestinal inflammation. We found that EGFR was activated in colonic macrophages in mice with dextran sulfate sodium (DSS)-induced colitis and in patients with ulcerative colitis. DSS-induced acute colitis was ameliorated, and recovery from colitis was promoted in Egfr(fl/fl)LysM-Cre mice with myeloid cell-specific deletion of EGFR, compared with LysM-Cre mice. DSS treatment increased IL-10 and TNF levels during the acute phase of colitis, and increased IL-10 but reduced TNF levels during the recovery phase in Egfr(fl/fl)LysM-Cre mice. An anti-IL-10 neutralizing Ab abolished these effects of macrophage-specific EGFR deletion on DSS-induced colitis in Egfr(fl/fl)LysM-Cre mice. LPS stimulated EGFR activation and inhibition of EGFR kinase activity enhanced LPS-stimulated NF-κB activation in RAW 264.7 macrophages. Furthermore, induction of IL-10 production by EGFR kinase-blocked RAW 264.7 cells, in response to LPS plus IFN-γ, correlated with decreased TNF production. Thus, although selective deletion of EGFR in macrophages leads to increases in both pro- and anti-inflammatory cytokines in response to inflammatory stimuli, the increase in the IL-10 level plays a role in suppressing proinflammatory cytokine production, resulting in protection of mice from intestinal inflammation. These results reveal an integrated response of macrophages regulated by EGFR in intestinal inflammatory disorders.
authors.affiliation: Department of Breast Cancer Medical Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P. R. China;
authors.forename: Ning
authors.initials: N
authors.lastname: Lu
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.forename: Hailong
authors.initials: H
authors.lastname: Cao
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: Philip E
authors.initials: PE
authors.lastname: Dubé
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.forename: Xishan
authors.initials: X
authors.lastname: Hao
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000276:immunology / Q000473:pathology / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012038:Regeneration; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology; D055815:Young Adult
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; D016753:Interleukin-10; C101044:RTKI cpd; D007371:Interferon-gamma; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors