Immune Regulation of Protease-Activated Receptor-1 Expression in Murine Small Intestine during Nippostrongylus brasiliensis Infection

• Published in: The Journal of immunology (1950) 2005-08, Vol.175 (4), p.2563-2569
• Main Authors: Zhao, Aiping, Morimoto, Motoko, Dawson, Harry, Elfrey, Justin E, Madden, Kathleen B, Gause, William C, Min, Booki, Finkelman, Fred D, Urban, Joseph F. Jr, Shea-Donohue, Terez
• Format: Article
• Language: English
• Subjects: Animals; Dose-Response Relationship, Drug; Female; gene expression; immune response; Interleukin-13 - administration & dosage; Interleukin-13 - deficiency; Interleukin-13 - physiology; Interleukin-4 - deficiency; Interleukin-4 - genetics; Interleukin-4 - physiology; Jejunum - drug effects; Jejunum - immunology; Jejunum - metabolism; Jejunum - parasitology; messenger RNA; Mice; Mice, Inbred BALB C; Mice, Knockout; muscle contraction; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Nematoda; nematode infections; Nippostrongylus - immunology; Nippostrongylus brasiliensis; Oligopeptides - pharmacology; protease-activated receptor-1; proteinases; Receptor, PAR-1 - agonists; Receptor, PAR-1 - biosynthesis; Receptor, PAR-1 - metabolism; receptors; small intestine; smooth muscle; STAT6 Transcription Factor - deficiency; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - physiology; Strongylida Infections - immunology; Strongylida Infections - metabolism; Up-Regulation - immunology
• ISSN: 1550-6606; 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.4.2563

Infection with gastrointestinal nematodes exerts profound effects on both immune and physiological responses of the host. Helminth infection induces a hypercontractility of intestinal smooth muscle that is dependent on the Th2 cytokines, IL-4 and IL-13, and may contribute to worm expulsion. Protease-activated receptors (PARs) are expressed throughout the gut, and activation of PAR-1 was observed in asthma, a Th2-driven pathology. In the current study we investigated the physiologic and immunologic regulation of PAR-1 in the murine small intestine, specifically 1) the effect of PAR-1 agonists on small intestinal smooth muscle contractility, 2) the effects of Nippostrongylus brasiliensis infection on PAR-1 responses, 3) the roles of IL-13 and IL-4 in N. brasiliensis infection-induced alterations in PAR-1 responses, and 4) the STAT6 dependence of these responses. We demonstrate that PAR-1 activation induces contraction of murine intestinal smooth muscle that is enhanced during helminth infection. This hypercontractility is associated with an elevated expression of PAR-1 mRNA and protein. N. brasiliensis-induced changes in PAR-1 function and expression were seen in IL-4-deficient mice, but not in IL-13- or STAT6-deficient mice, indicating the dependence of IL-13 on the STAT6 signaling pathway independent of IL-4.