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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

Authors

  • Munitz A
  • Waddell A
  • Seidu L
  • Cole ET
  • Ahrens R
  • Hogan SP
  • Rothenberg ME

Journal

The Journal of allergy and clinical immunology

Publication Data

December 16, 2008

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL-076383
  • Agency: NHLBI NIH HHS, Id: P01 HL076383
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-010003
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-019002
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-020003
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-029002
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-030003
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-039002
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-040003
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-049002
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-050003
  • Agency: NHLBI NIH HHS, Id: P01 HL076383-059002
  • Agency: NIAID NIH HHS, Id: R01 AI057803
  • Agency: NIAID NIH HHS, Id: R01 AI057803
  • Agency: NIAID NIH HHS, Id: R01 AI057803-01
  • Agency: NIAID NIH HHS, Id: R01 AI057803-02
  • Agency: NIAID NIH HHS, Id: R01 AI057803-03
  • Agency: NIAID NIH HHS, Id: R01 AI057803-04
  • Agency: NIAID NIH HHS, Id: R01 AI073553
  • Agency: NIAID NIH HHS, Id: R01 AI073553-01A1

Mesh Terms

  • 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