Enteric expression of the integrin alpha(v)beta(6) is essential for nematode-induced mucosal mast cell hyperplasia and expression of the granule chymase, mouse mast cell protease-1.
The immunoregulatory cytokine transforming growth factor (TGF)-beta(1) is secreted as a biologically inactive complex with latency-associated peptide, which must be modified by local factors to expose the functionally active cytokine. The epithelial integrin alpha(v)beta(6) mediates local activation of TGF-beta(1) in the lung and beta(6)(-/-) mice exhibit exaggerated pulmonary inflammation, but their response to inflammatory stimuli in the gut has not been investigated. We found that both beta(6) and TGF-beta(1) are constitutively expressed in the jejunal epithelial compartment in uninfected mice and during infection with the intestinal nematode Nippostrongylus brasiliensis. We also present data showing that beta(6)(-/-) mice are seriously compromised in their ability to mount a mucosal mast cell response after infection, and there is a significant reduction in the expression and systemic release of the granule chymase, mouse mast cell protease-1. Because in vitro expression of this chymase is regulated by TGF-beta(1), these data indicate that in the absence of alpha(v)beta(6) epithelially expressed TGF-beta(1) may not be activated, with a consequent absence of expression of mouse mast cell protease-1 and down-regulation of the mucosal mast cell response.
Knight
Pamela A
PA
Department of Veterinary Clinical Studies, University of Edinburgh, Midlothian, Scotland. pam.knight@ed.ac.uk
Wright
Steven H
SH
Brown
Jeremy K
JK
Huang
Xiaozhu
X
Sheppard
Dean
D
Miller
Hugh R P
HR
D000818:Animals; D000951:Antigens, Neoplasm; D053818:Chymases; D015536:Down-Regulation; D006801:Humans; D006965:Hyperplasia; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D008822:Mice, Transgenic; D009559:Nippostrongylus; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D017206:Strongylida Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D012697:Serine Endopeptidases; D053818:Chymases; C509230:Mcpt1 protein, mouse