Nature Medicine
6, 151 - 158 (2000)
doi:10.1038/72247
Agonists of proteinase-activated receptor 2 induce inflammation by a
neurogenic mechanismM. Steinhoff1, 7, N. Vergnolle4, 7, S.H. Young3, 7, M. Tognetto6, 7, S. Amadesi6, H.S. Ennes3, M. Trevisani6, M.D. Hollenberg4, J.L. Wallace4, G.H. Caughey2, S.E. Mitchell5, L.M. Williams5, P. Geppetti6, E.A. Mayer3
& N.W. Bunnett11
Departments of Surgery and Physiology, University of
California, 513 Parnassus Avenue, San Francisco
, California 94143, USA
2
Department of Medicine and the Cardiovascular Research
Institute, University of California, San Francisco,
California 94143, USA
3
Department of Medicine and CURE VA/UCLA Digestive Diseases
Research Center, University of California, Los Angeles,
California 90073, USA
4
Department of Pharmacology and Therapeutics, University
of Calgary, Calgary, AB T2N 4N1, Canada
5
Rowett Research Institute, Aberdeen
LS21 9JT, UK
6
Department of Experimental and Clinical Medicine, Headache
Center, Pharmacology Section, University of Ferrara, 44100
Ferrara, Italy
7
M.S., N.V., S.H.Y. and M.T. contributed equally to this
study.
Correspondence should be addressed to N.W. Bunnett nigelb@itsa.ucsf.eduTrypsin and mast cell tryptase cleave proteinase-activated receptor 2 and,
by unknown mechanisms, induce widespread inflammation. We found that a large
proportion of primary spinal afferent neurons, which express proteinase-activated
receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related
peptide and substance P. Trypsin and tryptase directly signal to neurons to
stimulate release of these neuropeptides, which mediate inflammatory edema
induced by agonists of proteinase-activated receptor 2. This new mechanism
of protease-induced neurogenic inflammation may contribute to the proinflammatory
effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists
of proteinase-activated receptor 2 may be useful anti-inflammatory agents.
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