The evolution of host defense to combat a multitude of pathogens is characterized, in part, by polarization towards either the Th1 or Th2 cytokine profile. It is known that pathogen-induced up-regulation of Th1 versus Th2 cytokines induces stereotypic and sometimes opposing changes in gut smooth muscle and epithelial cell responses that are important for host resistance. The imbalance of Th1/Th2 cytokines, with over-expression of Th1 cytokines, is associated with dysregulated gut function and is a characteristic of a number of mucosal inflammatory conditions of the gut including inflammatory bowel disease (IBD). The long term objective of our studies is to understand how up-regulation of specific cytokine profiles impacts gut function and contributes to host resistance against enteric pathogens. In the previous grant period we determined that 1) nematode- induced up-regulation of Th2 cytokines induced stereotypic STAT6-dependent changes in smooth muscle and epithelial cell responses that were important for host resistance;2) IL-4 and IL-13, were able to bind to receptors on structural cells and activate STAT6 signaling pathways;3) activation of STAT6 signaling resulted in up-regulation of genes that affect function;and 4) cytokine receptor expression was different in the small intestine and colon and is altered by infection. We also showed that the Th1 cytokines exert STAT4- dependent effects on smooth muscle that were opposite to those induced by Th2 cytokines. Moreover, prior nematode infection provided an immune-mediated protection against colitis along with improved colonic function. Our preliminary data led us to focus our efforts in this proposal on the specific mechanisms by which enteric infection alters gut function. The proposed studies contain 3 specific aims that are designed to test the following two central hypotheses: 1) infection-induced development and duration of changes in gut function are mediated by direct effects of cytokines on structural cells and on the interaction between structural and immune cells (Specific Aims 1 and 2);and 2) members of the IL-17 cytokine family are important in regulation of the functional effects associated with the Th1 or Th2 profiles (Specific Aim 3). The proposed approach will use mice infected with natural rodent pathogens, in vivo and in vitro studies of mucosal and smooth muscle function, primary cultures of immune cells, and molecular and immunohistochemical analyses. These studies will help us to understand how the host exploits physiological mechanisms in its defense against pathogens that allow for the stereotypic functional responses that promote expulsion. The impact of these studies is evident in that dysregulation of these functional changes significantly impairs host resistance and the maintenance of adequate barrier function and nutrient absorption. These studies also will provide insight on the mechanisms involved in the ability of nematode infection to protect against the development of autoimmune diseases, many of which are characterized by impaired intestinal barrier function. Project Narrative The rising prevalence of IBD is mirrored by the decreasing incidence of helminth infection, suggesting a relationship between the epidemiology of these diseases based, in part, on the polarity of Th cell responses. As one of the major regulatory mechanisms in the immune system is control of the balance of cytokines, both enteric infection and IBD are considered excellent targets for immunomodulatory therapies. Some nematodes induce an elevation of Th2 cytokines, including IL-4 and IL-13, which are linked to protective immunity against worm infection. Although a current therapeutic target in IBD is reduction of Th1 cytokine activity, an alternate approach is to rectify the Th1/Th2 cytokine imbalance by increasing Th2 cytokines. The recent clinical success of therapies directed at targeting Th2 cytokines provides a more specific therapeutic approach to the treatment of IBD than that offered by the standard anti-inflammatory and anti-immune regimens. Infection- induced up-regulation of Th2 and Th1 cytokines have a significant impact on gut function that is important to host resistance. The significance of the proposed studies is that they address how immune and structural cells interact to regulate gut function. The impact of these studies is based on identification potential therapeutic targets of benefit to pathologies associated with dysregulation of Th1 or Th2 responses.
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