Received 16 March 2006; received in revised form 7 April 2006; accepted 10 April 2006.
Background
Resistin-like molecule (RELM) β is a cysteine-rich cytokine expressed in the gastrointestinal tract and implicated in insulin resistance and gastrointestinal nematode immunity; however, its function primarily remains an enigma.
Objective
We sought to elucidate the function of RELM-β in the gastrointestinal tract.
Methods
We generated RELM-β gene–targeted mice and examined colonic epithelial barrier function, gene expression profiles, and susceptibility to acute colonic inflammation.
Results
We show that RELM-β is constitutively expressed in the colon by goblet cells and enterocytes and has a role in homeostasis, as assessed by alterations in colon mRNA transcripts and epithelial barrier function in the absence of RELM-β. Using acute colonic inflammatory models, we demonstrate that RELM-β has a central role in the regulation of susceptibility to colonic inflammation. Mechanistic studies identify that RELM-β regulates expression of type III regenerating gene (REG) (REG3β and γ), molecules known to influence nuclear factor κB signaling.
Conclusions
These data define a critical role for RELM-β in the maintenance of colonic barrier function and gastrointestinal innate immunity.
Clinical implications
These findings identify RELM-β as an important molecule in homeostatic gastrointestinal function and colonic inflammation, and as such, these results have implications for a variety of human inflammatory gastrointestinal conditions, including allergic gastroenteropathies.
Cincinnati, Ohio, Tarrytown, NY, and Philadelphia, Pa
aFrom the Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
bDepartment of Immunobiology, University of Cincinnati College of Medicine
dDepartment of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia
Reprint requests: Marc E. Rothenberg, MD, PhD, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, ML7028, Cincinnati OH 45229.
Supported in part by the DDRDC Pilot and Feasibility Grant (NIH R24 DK64403; S.P.H.), R01 AI42242 (M.E.R.), AI45898 (M.E.R.), AI53479 (M.E.R.), and the Burroughs Wellcome Fund (M.E.R.) RO1 AI61570 (D.A.) and the Crohn's and Colitis Foundation of America's William and Shelby Modell Family Foundation Research Award (D.A.), and T32 AI060515 (L.S.).
Disclosure of potential conflict of interest: A. Mishra has received grant support from the National Institutes of Health. A. J. Murphy owns stock in and is employed by Regeneron Pharmaceuticals, Inc. M. E. Rothenberg owns stock in Ception Therapeutics, is the inventor of a patent application filed by CCHMC concerning RELM-β, has received grant support from Cambridge Antibody Technology, and is on the speakers' bureau for Merck. The rest of the authors have declared that they have no conflict of interest.
ABSTRACT