TY - JOUR
T1 - Resistin-like molecule α enhances myeloid cell activation and promotes colitis
AU - Munitz, Ariel
AU - Waddell, Amanda
AU - Seidu, Luqman
AU - Cole, Eric T.
AU - Ahrens, Richard
AU - Hogan, Simon P.
AU - Rothenberg, Marc E.
PY - 2008/12
Y1 - 2008/12
N2 - Background: Resistin-like molecule (Relm) α is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-α is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-α remains unknown. Objective: We sough to determine the role of Relm-α in dextran sodium sulfate (DSS)-induced colonic injury. Methods: The cellular source of Relm-α 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-α was assessed. Relm-α was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed. Results: After innate intestinal stimulation with DSS, Relm-α 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-α coactivated IL-6 and TNF-α 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-α initiated cellular recruitment to the peritoneum, and Relm-α was able to induce eosinophil chemotaxis in vitro. Conclusions: These findings demonstrate a central proinflammatory role for Relm-α in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation.
AB - Background: Resistin-like molecule (Relm) α is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-α is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-α remains unknown. Objective: We sough to determine the role of Relm-α in dextran sodium sulfate (DSS)-induced colonic injury. Methods: The cellular source of Relm-α 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-α was assessed. Relm-α was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed. Results: After innate intestinal stimulation with DSS, Relm-α 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-α coactivated IL-6 and TNF-α 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-α initiated cellular recruitment to the peritoneum, and Relm-α was able to induce eosinophil chemotaxis in vitro. Conclusions: These findings demonstrate a central proinflammatory role for Relm-α in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation.
KW - LPS
KW - Resistin-like molecule α
KW - colitis
KW - eosinophils
KW - inflammation
KW - inflammatory bowel disease
KW - macrophages
UR - http://www.scopus.com/inward/record.url?scp=57149126819&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2008.10.017
DO - 10.1016/j.jaci.2008.10.017
M3 - מאמר
AN - SCOPUS:57149126819
VL - 122
SP - 1200-1207.e1
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -