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and Infection-Induced Intestinal Inflammation1
* Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104;
Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and
Amgen, Thousand Oaks, CA 91320
The secreted goblet cell-derived protein resistin-like molecule β (RELMβ) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMβ influences CD4+ T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMβ in augmenting CD4+ Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-
production and intestinal inflammation. In contrast, infected RELMβ–/– mice exhibited a significantly reduced expression of parasite-specific CD4+ T cell-derived IFN- and TNF-
and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMβ activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN- expression in CD4+ T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMβ, can promote adaptive CD4+ T cell responses and chronic inflammation following intestinal helminth infection.
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 This work was supported by National Institutes of Health Grants AI61570 and AI74878 (to D.A.), the Burroughs Wellcome Fund’s Investigator in Pathogenesis of Infectious Disease Award (to D.A.), the Crohn’s and Colitis Foundation of America’s William and Shelby Modell Family Foundation Research Award (to D.A.), and pilot grants from the University of Pennsylvania Center for Infectious Diseases and University Research Fund (to D.A.). C.Z. is funded by the Irvington Institute Fellowship Program of the Cancer Research Institute.
2 Address correspondence and reprint requests to Dr. David Artis or Dr. Meera G. Nair, Department of Pathobiology, University of Pennsylvania, Room 314, Hill Pavilion, 380 South University Avenue, Philadelphia, PA 19104. E-mail addresses: dartis{at}vet.upenn.edu or nairmg{at}vet.upenn.edu
3 Abbreviations used in this paper: IEC, intestinal epithelial cell; RELMβ, resistin-like molecule β; BM, bone marrow; MLN, mesenteric lymph node; WT, wild type; MFI, mean fluorescent intensity; DC, dendritic cell.
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