Immune regulation of protease-activated receptor-1 expression in murine small intestine during Nippostrongylus brasiliensis infection.
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.
Zhao
Aiping
A
Department of Medicine and the Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Morimoto
Motoko
M
Dawson
Harry
H
Elfrey
Justin E
JE
Madden
Kathleen B
KB
Gause
William C
WC
Min
Booki
B
Finkelman
Fred D
FD
Urban
Joseph F
JF
Shea-Donohue
Terez
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018793:Interleukin-13 / Q000008:administration & dosage / Q000172:deficiency / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007583:Jejunum / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009559:Nippostrongylus / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000096:biosynthesis* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017206:Strongylida Infections / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D018793:Interleukin-13; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D050800:STAT6 Transcription Factor; D015847:Interleukin-4