Submitted to: Journal of Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 5/20/2003
Publication Date: 7/27/2003
Citation: Zhao, A., Mcdermott, J., Urban Jr, J.F., Gause, W., Madden, K., Auyeung, K., Morris, S., Finkelman, F., Shea-Donohue, T. 2004. Dependence of i1-4, il-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on stat6 and enteric nerves. Journal of Immunology. 171:948-954 (2003). Interpretive Summary: Intestinal worm parasites infect over one billion people worldwide and cause significant economic losses in livestock. The parasites interfere with how a person can use nutrients and need activation of the immune system to eliminate the infection. A detailed examination of how smooth muscle lining the gut contracts during infection with worms can provide information on how to control infection as well as restore normal digestion in the gut. Two particular agents that have similar function on smooth muscle cells were examined in detail. These were interleukin-4 (IL-4) and IL-13. These molecules were shown to increase smooth muscle contractility to nerve stimulation in untreated mice with IL-13 having a greater effect. This effect was not present in mice without Stat6, a molecule needed in cell regulation. Mice infected with worm parasites also showed increased smooth muscle contractility again dependent on the presence of Stat6. Additionally, worm-infected and IL-13-induced contractility was blocked with a neurotoxin, supporting that this effect is due to nerves. These results suggest that IL-4 and IL-13 increase smooth muscle contractility by different mechanisms. This work will primarily benefit scientist in academia, industry and government laboratories that want to provide successful vaccination strategies against worm parasites without appreciable affecting metabolism and growth.
Technical Abstract: IL-4 and IL-13 promote gastrointestinal worm expulsion through effects on non-lymphoid cells, such as intestinal smooth muscle cells. The roles of Stat6 in IL-4, IL-13, and parasitic nematode-induced effects on small intestinal smooth muscle contractility were investigated in BALB/c WT and Stat6-deficient mice treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or IL-13 for seven days. Separate groups of mice were infected with Nippostrongylus brasiliensis or drug-cured of an initial Heligmosomoides polygyrus infection and later re-infected. Infected mice were studied at 9 and 12 days after inoculation. Segments of jejunum were suspended in an organ bath and responses to nerve stimulation and to acetylcholine and substance P in the presence and absence of tetrodotoxin were determined. Both IL-4 and IL-13 increased smooth muscle responses to nerve stimulation in wild type mice, but the effects were greater in IL-13 treated mice and were absent in IL-13 treated Stat6 deficient mice. Similarly, hyper contractile responses to nerve stimulation in Heligmosomoides polygyrus and Nippostrongylus brasiliensis infected mice were dependent, in part, on Stat6. IL-13, Heligmosomoides polygyrus and Nippostrongylus brasiliensis, but not IL-4, increased contractility to acetylcholine by mechanisms that involved Stat6 and enteric nerves. These studies demonstrate that both IL-4 and IL-13 promote intestinal smooth muscle contractility, but by different mechanisms. Differences in these effects correlate with differences in the relative importance of these cytokines in the expulsion of enteric nematode parasites.