|Setiawan, Tommy - UNIVERSITY OF IOWA|
|Metwali, Ahmed - " "|
|Blum, Authur - " "|
|Elliott, David - UNIVERSITY OF IOWA|
|Weinstock, Joel - " "|
Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 15, 2006
Publication Date: July 2, 2007
Citation: Setiawan, T., Metwali, A., Blum, A., Urban Jr, J.F., Elliott, D., Weinstock, J. 2007. Heligmosomoides polygyrus promotes T regulatory cytokine production in the normal distal murine intestine. Infection and Immunity. 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 studies use a mouse model to examine the tissue response to worm infection in the intestine along with the changes that are expressed after a chemically induced colitis in the distal intestine. The worm does not cause severe reactions in the part of the intestine where it resides and, in fact, reduces the intensity of tissue damage in the distal intestine that is treated with a noxious chemical. In addition, it is shown that cells from the worm-infected animal can transfer the property of disease reduction when given to another mouse expressing colitis. The cells produce protein mediators that are important in the palliative process. 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 down-regulate inflammatory reactions and may prevent inflammatory bowel disease. Helminths protect mice and rats from TNBS-induced colitis. Our aim was to determine if exposure to the duodenal helminth H. polygyrus establishes cytokine pathways in distal intestinal mucosa that may protect from intestinal inflammation. Mice received 200 H. polygyrus larvae by oral gavage and were studied 2 wks later. H. polygyrus did not change the normal microscopic appearance of terminal ileum and colon, and minimally affected LPMC composition. However, colonization altered LPMC cytokine profiles, blocking IFN-gamma and IL12 p40 release, but promoting IL4, IL5, IL13, IL10, TGF-beta and PgE2 secretion. Production of IFN-gamma, IL4, IL5, IL10, TGF-beta and much of the PgE2 were T cell-dependent. Cytokine blocking experiments determined if worm-induced cytokines actively suppressed LP IFN-gamma and IL12 p40 production. IL10 blockade in-vitro with anti-IL10R mAb restored LPMC IFN-gamma and IL12 p40 secretion to near normal levels. H. polygyrus also induced FoxP3 expression in LP T cells. Mice colonized with H. polygyrus were resistant to TNBS colitis, which is a Th1 cytokine-dependent inflammation. It is concluded that duodenal colonization with an intestinal helminth inhibits Th1 and promotes Th2 and regulatory cytokine production in distant intestinal regions without significantly changing histology or LPMC composition. The T cell origin of these cytokines and the induction of FoxP3 suggest regulatory T cell induction as well. IL10 appears to be particularly important for limiting the Th1 response.