Resistin-like molecule alpha enhances myeloid cell activation and promotes colitis.
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, Retnla(-/-) 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.
Pubmed ID: 19084112 RIS Download
Animals | Bone Marrow Cells | Chemotaxis | Colitis | Colon | Cytokines | Dextran Sulfate | Eosinophils | Female | Intercellular Signaling Peptides and Proteins | JNK Mitogen-Activated Protein Kinases | Lipopolysaccharides | Macrophage Activation | Macrophages | Male | Mice | Mice, Inbred BALB C | Mice, Knockout | Organ Culture Techniques | Peritoneum | Phosphorylation