|Liu, Qian - DEPT.MED.,UMDNJ,NEWARK,NJ|
|Liu, Zhugong - DEPT.MED.UMDNJ, NEWARK,NJ|
|Whitmire, Jeannette - USUHS, BEHTESDA, MD|
|Alem, Farhang - DEPT. MED.,UMDNJ, NJ|
|Hamed, Hossein - DEPT.MED.,UMDNJ,NEWARK,NJ|
|Pesce, John - USUHS, BETHESDA, MD|
|Gause, W - DEPT. MD. UMDNJ,NEWARK NJ|
Submitted to: European Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 15, 2006
Publication Date: May 1, 2006
Citation: Liu, Q., Liu, Z., Whitmire, J., Alem, F., Hamed, H., Pesce, J., Urban Jr, J.F., Gause, W. 2006. IL-18 stimulates IL-13 mediated INF-gamma sensitive host resistance in vivo. European Journal of Immunology. 36(5):1187-1198. Interpretive Summary: Immunity to worm parasites is complex, but generally express as immediate type reactions that expel the worms from the intestine without severe or long lasting effects on host intestinal function. The molecular events that are necessary to trigger this response are critical for the production of appropriate vaccines against infectious agents or for strategies to improve the general health of the individuals affected by disease, and nutrient and immune deficiencies. The current study uses an experimental mouse model of an infection with a gastrointestinal worm parasite that directly invades the large bowel and induces responses in the draining lymph nodes that regulate production of the messenger protein IL-13 that is a critical activator of the protective response to this infection. We were able to identify the cellular source of IL-13, and how expression of other protein cytokines such as interferon gamma and IL-18 can regulate the activity of IL-13 and the resistance to infection. IL-13 is also important in the physiological absorption and metabolism of nutrients in the intestine; and its regulation is important to restoring balance in the gut to control infection while maintaining appropriate nutrient utilization. This information will be important to scientists interested in control of parasitic infection, and nutritionists that study how immunity can affect nutrient utilization.
Technical Abstract: Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, resulting in the development of an IFN-gamma dominant response associated with susceptibility. However, blocking IFN-gamma under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 up regulation and associated protection during this in vivo immune response. Using magnetic beads and electronic cell-sorting as well as quantitative RT-PCR, CD4+ T cells and DX5+ TCR- cells were identified as the major producers of IL-13. Flow cytometric analysis characterized these DX5+ TCR- cells as NK cells since they expressed CD11b, IL-2R alpha, Ly49C, but not c-kit and Fc epsilon RI. NK-cell derived IL-13 elevations were T cell dependent as CD4+ T cell depletion blocked IL-13 production by MLN cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions IL-18, but not IL-12, is specifically required for the in vivo up regulation of IL-13 production and associated host protection.