Resistin-like molecule β regulates innate colonic function:: Barrier integrity and inflammation susceptibility

Background: Resistin-like molecule (RELM) P 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-beta in the gastrointestinal tract. Methods: We generated RELM-beta gene-targeted mice and examined colonic epithelial barrier function, gene expression profiles, and susceptibility to acute colonic inflammation. Results: We show that RELM-P 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-P. Using acute colonic inflammatory models, we demonstrate that RELM-beta has a central role in the regulation of susceptibility to colonic inflammation. Mechanistic studies identify that RELM-beta regulates expression of type III regenerating gene (REG) (REG3 beta and gamma), molecules known to influence nuclear factor kappa B signaling. Conclusions: These data define a critical role for RELM-P in the maintenance of colonic barrier function and gastrointestinal innate immunity. Clinical implications: These findings identify RFLM-beta 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.