期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 122, 期 6, 页码 1200-1207出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2008.10.017
关键词
Resistin-like molecule alpha; colitis; macrophages; eosinophils; LPS; inflammation; inflammatory bowel disease
资金
- National Institutes of Health [P01 HL-076383, R01 AI057803]
- Machiah Foundation
- Jewish Community Endowment Fund
- Alexander M. and June L. Maisin Foundation
- Kanbar Charitable Trust
- Campaign Urging Research for Eosinophilic Disorders (CURED)
- Food Allergy Project
- Buckeye Foundation
- Food Allergy and Anaphylaxis Network
- Dana Foundation
Background: Resistin-like molecule (Relm) alpha is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-alpha is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-alpha remains unknown. Objective: We sough to determine the role of Relm-alpha in dextran sodium sulfate (DSS)-induced colonic injury. Methods: The cellular source of Relm-alpha was determined after oral DSS-induced colitis. Retnla(-/-) mice were generated, subjected to DSS treatment, and monitored for disease progression (clinical and histopathologic features). Cytokine production in the supernatants of ex vivo colon cultures, and of LPS-stimulated macrophages incubated with Relm-alpha was assessed. Relm-alpha was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed. Results: After innate intestinal stimulation with DSS, Relm-alpha was highly expressed by eosinophils and epithelial cells. Retnla gene-targeted mice were protected from DSS-induced colitis (eg, decreased diarrhea, rectal bleeding, colon shortening, disease score, and histopathologic changes). Relm-alpha coactivated IL-6 and TNF-alpha release and inhibited IL-10 release from LPS-activated bone marrow-derived macrophages. Consistent with these finding, colon cultures of DSS-treated Retnla(-/-) mice produced decreased IL-6 and increased IL-10 ex vivo. Furthermore, Retnta-l- mice had substantially decreased c-Jun N-terminal kinase phosphorylation in vivo. In vivo administration of Relm-alpha initiated cellular recruitment to the peritoneum, and Relm-alpha was able to induce eosinophil chemotaxis in vitro. Conclusions: These findings demonstrate a central proinflammatory role for Relm-alpha in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation. Q Allergy Clin Immunol 2008;122:1200-7.)
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