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IL-31-IL-31R Interactions Limit the Magnitude of Th2 Cytokine-Dependent Immunity and Inflammation following Intestinal Helminth Infection¹

Jacqueline G. Perrigoue^*, Colby Zaph, Katherine Guild^*, Yurong Du^* and David Artis^2,*

^* Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104; and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

IL-31 is a recently identified cytokine made predominantly by CD4⁺ Th2 cells and its receptor, IL-31R, is expressed by a number of cell types including monocytes, epithelial cells, and T cells. Originally identified as a potential mediator of inflammation in the skin, we recently reported a novel function for endogenous IL-31R interactions in limiting type 2 inflammation in the lung. However, whether IL-31-IL-31R interactions regulate immunity or inflammation at other mucosal sites, such as the gut, is unknown. In this study, we report a regulatory role for IL-31-IL-31R interactions in the intestine following infection with the gastrointestinal helminth Trichuris muris, immunity to which is critically dependent on CD4⁺ Th2 cells that produce IL-4 and IL-13. IL-31R was constitutively expressed in the colon and exposure to Trichuris induced the expression of IL-31 in CD4⁺ T cells. In response to Trichuris infection, IL-31R^–/– mice exhibited increased Th2 cytokine responses in the mesenteric lymph nodes and elevated serum IgE and IgG1 levels compared with wild type mice. IL-31R^–/– mice also displayed enhanced goblet cell hyperplasia and a marked increase in secretion of goblet cell-derived resistin-like molecule β into the intestinal lumen. Consistent with their exacerbated type 2 inflammatory responses, IL-31R^–/– mice exhibited accelerated expulsion of Trichuris with significantly decreased worm burdens compared with their wild type counterparts early following infection. Collectively, these data provide the first evidence of a function for IL-31-IL-31R interactions in limiting the magnitude of type 2 inflammatory responses within the intestine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Research in the Artis laboratory is supported by the National Institutes of Health (NIH), AI61570, AI 074878 (to D.A.), NIH T32 Training Grant AI 007532-08 (to J.P.), the Burroughs Wellcome Fund (Investigator in Pathogenesis of Infectious Disease Award to D.A.), the Pilot Feasibility Program of the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) DK50306, the Crohns and Colitis Foundation of America’s William and Shelby Modell Family Foundation Research Award, and pilot grants from the University of Pennsylvania (University Research Foundation Award, PGI Pilot Grant, and UPenn Center for Infectious Diseases Pilot Grant).

² Address correspondence and reprint requests to Dr. David Artis, Room 314 Hill Pavilion, University of Pennsylvania, 380 South University Avenue, Philadelphia PA 19104. E-mail address: dartis{at}vet.upenn.edu

³ Abbreviations used in this paper: OSM, oncostatin M; mLN, mesenteric lymph node; RELM, resistin-like molecule; WT, wild type.