Insulin modulates protease-activated receptor 2 signaling: Implications for the innate immune response

Authors

Eric Hyun, University of Calgary
Rithwik Ramachandran, University of Calgary
Nicolas Cenac, Hôpital Purpan
Steeve Houle, University of Calgary
Perrine Rousset, Hôpital Purpan
Amit Saxena, Hôpital Purpan
Roland S. Liblau, Hôpital Purpan
Morley D. Hollenberg, University of Calgary
Nathalie Vergnolle, University of Calgary

Document Type

Article

Publication Date

3-1-2010

Journal

Journal of Immunology

Volume

184

Issue

5

First Page

2702

Last Page

2709

URL with Digital Object Identifier

10.4049/jimmunol.0902171

Abstract

Given the anti-inflammatory effects of insulin in human and animal studies done in vivo and given the signaling pathways in common between insulin and the protease-activated receptor 2 (PAR2), a G protein-coupled receptor, we hypothesized that insulin would have an impact on the inflammatory actions of PAR2. We found that low doses or concentrations of insulin in the subnanomolar range reduced PAR2-induced inflammation in a murine paw edema model, attenuated PAR2-induced leukocyte trafficking in mouse intestinal venules, and reduced PAR2 calcium signaling in cultured dorsal root ganglion neurons and endothelial cells. This effect of insulin to attenuate PAR2-mediated inflammation was reversed when cells were preincubated with LY294002 (a PI3K inhibitor) and GF 109203X (a pan-protein kinase C inhibitor). The enhanced inflammatory effect of PAR2 observed in vivo in an insulin-deficient murine type 1 diabetes model was attenuated by the local administration of insulin at the inflammatory site. Our data point to an anti-inflammatory action of insulin that targets the acute innate inflammatory response triggered by PAR2. Copyright © 2010 by The American Association of Immunologists, Inc.