Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2005
Publication Date: 1/15/2006
Citation: Ince, N., Elliott, D., Setiawan, T., Blum, A., Metwali, A., Wang, Y., Urban, J., Weinstock, J. 2006. Heligmosomoides polygyrus induces TLR4 on murine mucosal T cells that produce TGFbeta after lipopolysaccharide stimulation. Journal of Immunology. 176(2):726-729
Interpretive Summary: Mouse models of inflammatory bowel disease (IBD) have shown that infection with worms can prevent or ameliorate intestinal colitis. These experimental models were designed to test the hypothesis that humans from industrialized Western countries with few worm infections express immune pathology that results in increased expression of IBD compared to lesser developed countries where worm infections are common and IBD is infrequent. The current study used a mouse model to examine the tissue response in the intestine to worm infection along with bacterial products called lipopolysaccharides (LPS). Humans with a defect in the receptor for LPS have increased risk of IBD. Worm infection conditioned cells expressing the LPS receptor in the mouse intestine to produce a regulatory molecule called TGF-beta when they were exposed to LPS. The release of TGF-beta has been shown to down regulate the inflammatory response, and represents a possible mechanism for reduced inflammation in the gut following infection with worms. This information is important to scientists and clinicians that explore treatment and prophylactic procedures to correct intestinal disorders, and for improved absorption of nutrients from the intestine. The impact will be related to better control procedures for inflammatory diseases of the intestine because specific cells and proteins have been identified that are critical to improving disease outcome.
Technical Abstract: Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGF-beta production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGF-beta, but not TNF-alpha or IL-12. The TGF-beta derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGF-beta secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGF-beta through a TLR4-dependent process without promoting synthesis of pro-inflammatory cytokines.