Submitted to: Science
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/12/2006
Publication Date: 12/15/2006
Citation: Zaiss, D.M., Yang, L., Shah, P.R., Kobie, J.J., Urban, J.F., Mosmann, T.R. 2006. Amphiregulin-a TH2 cytokine enhancing resistance to nematodes. Science. 314(5806):1746. Interpretive Summary: The spectrum of protein messengers molecules or cytokines that regulate immune function is the basis for host defense against infectious disease; however, cytokines can also affect non-immune functions and influence the physiology of the intestine. We examined the expression of Amphiregulin, a member of a family of proteins that generally regulate cell growth, in T lymphocytes that arise after parasitic infection and during allergic diseases. T cells from parasite infected mice will migrate to the intestine of naïve mice after injection and control the turn over of epithelial cells in the large intestine that is the site for infestation with the parasitic whipworm. Mice that have the gene for Amphiregulin removed or knocked out are more susceptible to infection and maintain worms for longer periods of time then when the gene is present in host intestinal tissue. Epithelial cell turnover in the intestine is important to the normal control of harmful bacteria and viruses that infect the intestine, as well as inflammatory response such as those seen in inflammatory bowel disorders. Understanding how circulating cells can home to the intestine and regulate local development and growth of epithelial cells is important as a control strategy for these diseases. This work will be of interest to nutritionists who study food allergy and scientists interested in the role of parasitic infection in host immunity, nutrient absorption, and inflammation of the gut.
Technical Abstract: Intestinal nematode infections remain a major health threat to humans despite improved sanitation. Protection is mainly mediated by Type 2-biased immune responses, characterized by Th2 lymphocytes and other cells secreting a set of cytokines including Interleukin 4 (IL-4), IL-5, IL-10, and IL-13. Increased shedding of the caecal epithelium is crucially important for the clearance of the intestinal nematode parasite Trichuris muris. Members of the epidermal growth factor (EGF) family can induce proliferation of the gut epithelium. GeneChip analysis of genes induced in different CD4 T cell subsets from C57BL/6 or BALB/c mice revealed that in vitro activation through the T cell antigen receptor induced preferential expression of the EGF family member Amphiregulin in Th2 cells, compared to naïve, Thpp or Th1 cells. Selective expression in Th2 cells was confirmed by Northern blot, RT-PCR and real-time PCR analysis. To test whether Amphiregulin was also expressed during a typical type 2 response in vivo, we infected C57BL/6 mice with Trichuris muris, and 14 days after infection analyzed cDNA from mesenteric lymph nodes by real-time PCR. Expression of the Th1 cytokine IFNg was reduced, while expression of IL-4, IL-13 and Amphiregulin was increased. Thus Amphiregulin expression parallels that of typical Th2 cytokines. Amphiregulin mRNA was also detected in the caecal tissue of infected Amphiregulin-/- mice that had received CD4 T-cells from Trichuris-infected wild-type mice; indicating that T cells expressing Amphiregulin could migrate to the intestine. Amphiregulin-/- mice had delayed clearance of Trichuris and reduced epithelial cell turnover in the intestine which could explain reduced resistance to whipworm.