Endothelin-1 stimulates human colonic myofibroblast contraction and migration.
BACKGROUND
Although the contractile, migratory, and proliferative responses of subepithelial myofibroblasts to injury have been postulated to be important events in intestinal wound healing, contractile force generation and migration by these cells has not been investigated previously, and the signals that regulate proliferation by these cells are poorly understood.


OBJECTIVE
The primary aim of this study was to test the hypothesis that the inflammatory mediator endothelin-1 modulates contraction, migration, and proliferation of intestinal myofibroblasts. We also sought to examine the signal transduction pathways which might underlie these putative effects.


METHODS
Contraction, migration, proliferation, cytosolic [Ca(2+)], and myosin phosphorylation were measured in human colonic subepithelial myofibroblasts in the absence and presence of endothelin receptor agonists and antagonists.


RESULTS
Endothelin-1, but not interleukin 1 alpha, interleukin 6, interleukin 8, interleukin 10, or tumour necrosis factor alpha, induced a rapid and robust generation of contractile force, which was associated with an increase in cytosolic [Ca(2+)] and myosin phosphorylation. Inhibition of rho associated kinase reduced endothelin-1 stimulated myosin phosphorylation and contractile force development. Endothelin-1 stimulated migration with a dose-response relationship similar to that observed for contraction. Endothelin A and B receptors mediated contraction while migration was mediated predominantly through endothelin B receptors. Platelet derived growth factor and serum, but not endothelin-1, induced proliferation.


CONCLUSIONS
Endothelin-1 stimulates colonic subepithelial myofibroblast contraction and migration via endothelin receptor mediated myosin phosphorylation. These results support an important role for subepithelial myofibroblasts in the injury response of the gut and consequently intestinal wound repair.
Kernochan
L E
LE
Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
Tran
B N
BN
Tangkijvanich
P
P
Melton
A C
AC
Tam
S P
SP
Yee
H F
HF
D000577:Amides / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000502:physiology*; D003600:Cytosol / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D007378:Interleukins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D009218:Myosins / Q000502:physiology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D054460:rho-Associated Kinases
D000577:Amides; D019332:Endothelin-1; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009218:Myosins