|Sutton, Thomas - PEDIATRICS,WALTER REED,DC|
|Zhao, Aiping - SCHOOL OF MED,BALTIMORE|
|Madden, Kathleen - UNIFORMED SVCS, BETHESDA|
|Elfrey, Justin - U OF MD SCHOOL OF MED|
|Tuft, Blaine - PEDIATRICS,WALTER REED,DC|
|Sullivan, Carolyn - PEDIATRICS,WALTER REED,DC|
|Shea-Donohue, Terez - SCHOOL OF MED,BALTIMORE|
Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 1, 2008
Publication Date: July 21, 2008
Citation: Sutton, T.L., Zhao, A., Madden, K.B., Elfrey, J.E., Tuft, B.A., Sullivan, C.A., Urban Jr, J.F., Shea-Donohue, T. 2008. Anti-inflammatory mechanisms of enteric Heligmosomoides polygyrus infection on TNBS-induced colitis in a murine model. Infection and Immunity 76(10):4772-82. Interpretive Summary: The spectrum of immune regulated cytokines is the basis for host defense against infectious disease; however, cytokines can also affect non-immune function that influence the physiology of the intestine, and affect the absorption of nutrients. We examined the effect of local expression of cytokines in the intestine by exposure to a worm parasite that naturally infects mice, but causes little clinical harm. The nature of host/parasite interactions, the factors that modulate susceptibility to infection, and the impact of enteric parasites on intestinal function are a few of the areas of research that hold much promise for development of novel preventative strategies to correct unregulated disease expression in the intestine. We observed that exposure of mice to a natural worm inoculation prevented chemically induced colitis by improving barrier function and affecting the expression of several components that regulate secretion and the loss of water from the body. This work will be of interest to nutritionists who study inflammatory bowel diseases and scientists interested in the role of parasitic infection in host immunity and nutrient absorption.
Technical Abstract: To model the protective mechanism of helminth infection on colitis-induced changes in immune and epithelial cell function, BALB/c mice received intra-rectal saline or TNBS (2 mg/mouse; 40% ETOH) and were studied 4 days (d) later. Separate groups of mice received oral Heligmosomoides polygyrus followed by intra-rectal saline or TNBS on 10d and were studied on 14d. Muscle-free colonic mucosae mounted in Ussing chambers to measure mucosal permeability and secretion to serotonin (5-HT), histamine, acetylcholine, and PAR-1 or PAR-2 agonists. Colonic expression of IFN-gamma, TNF-alpha, IL-13, IL-4, PAR-1, PAR-2, and the histamine-1 and -4 receptors (H1R and H4R, respectively) was assessed by quantitative real-time PCR. Immune fluorescence was used to detect mast cells. The results showed that TNBS up-regulated IFN-gamma, TNF-alpha, and H4R expression, down-regulated H1R expression, induced mucosal damage, and depressed secretory responses to 5-HT and histamine. Heligmosomoides polygyrus elevated IL-13 and IL-4 expression, increased mast cell infiltration, down-regulated H1R expression, decreased mucosal permeability and responses to PAR-1 and histamine, prevented TNBS-induced up-regulation of Th1 cytokines and H4R expression, and normalized secretory responses to 5-HT and PAR-2. TNBS decreased the H. polygyrus-induced mast cell infiltration but did not affect its decreased mucosal permeability and increased Th2 cytokine expression. Expression of both PARs and the secretory response to acetylcholine were unchanged in all groups. The protective mechanism of enteric infection against TNBS-induced colitis involves down-regulation of local inflammatory mediator expression and improved colonic function.