Protective effects of neurokinin-1 receptor during colitis in mice: role of the epidermal growth factor receptor.
1. The role of substance P and its high affinity neurokinin-1 receptor in colitis has not been fully elucidated. We assessed the participation of neurokinin-1 receptor in colitis using the 2,4,6,-trinitrobenzensulphonic acid and dextran sulphate-induced animal models of colitis and genetically-engineered, neurokinin-1 receptor-deficient mice. 2. Clinical signs, macroscopic and histologic damage associated with 2,4,6,-trinitrobenzensulphonic acid (12 days) and dextran sulphate (5 days) colitis were more severe in neurokinin-1 deficient than in wild-type mice, while immunoreactivities for epidermal growth factor and its receptor were similar in the colon of both mice strains before and after colitis. 3. Substance P, dose-dependently induced intestinal fibroblast proliferation and enhanced epidermal growth factor-induced proliferation in intestinal fibroblasts isolated from wild-type, but not from neurokinin-1 receptor deficient mice. 4. Substance P-induced intestinal fibroblast proliferation required the presence of epidermal growth factor receptor with kinase activity. Furthermore, substance P induced epidermal growth factor tyrosine phosphorylation and activation in normal intestinal fibroblasts. 5. Our results indicate that in mice lacking the neurokinin - 1 receptor, substance P plays a protective role in prolonged experimental colitis.
Castagliuolo
I
I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, MA 02215, USA.
Morteau
O
O
Keates
A C
AC
Valenick
L
L
Wang
C-C
CC
Zacks
J
J
Lu
B
B
Gerard
N P
NP
Pothoulakis
C
C
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology
D018040:Receptors, Neurokinin-1; D013373:Substance P; D066246:ErbB Receptors