Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

M Steinhoff, N Vergnolle, S H Young, M Tognetto, S Amadesi, H S Ennes, M Trevisani, M D Hollenberg, J L Wallace, G H Caughey, Sharon Elizabeth Mitchell, Lynda Williams, P Geppetti, E A Mayer, N W Bunnett

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729 Citations (Scopus)


Trypsin 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.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalNature Medicine
Issue number2
Publication statusPublished - Feb 2000


  • gene-related peptide
  • mast-cell tryptase
  • spinal dorsal horn
  • substance-P
  • endothelial-cells
  • thrombin receptor
  • in-vitro
  • skin
  • vasodilator
  • CGRP

Cite this

Steinhoff, M., Vergnolle, N., Young, S. H., Tognetto, M., Amadesi, S., Ennes, H. S., Trevisani, M., Hollenberg, M. D., Wallace, J. L., Caughey, G. H., Mitchell, S. E., Williams, L., Geppetti, P., Mayer, E. A., & Bunnett, N. W. (2000). Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Medicine, 6(2), 151-158.