Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.
An increase in myofibroblast number may be necessary for wound healing but may also lead to postinflammatory scarring. We have, therefore, studied the role of mediators important in inflammatory bowel disease in regulating proliferation of human colonic myofibroblasts. Using primary cultures of these cells, we have shown increases in [3H]thymidine incorporation in response to platelet-derived growth factor (EC50 = 14 ng/ml), basic fibroblast growth factor (EC50 = 2.2 ng/ml), and epidermal growth factor (EC50 = 1.1 ng/ml). Coulter counting of cell suspensions demonstrated increases in cell number with these growth factors along with insulin-like growth factor-I and -II. In addition the proinflammatory cytokines IL-1beta and TNF-alpha produced increases in [3H]thymidine incorporation. IL-1beta and platelet-derived growth factor together produced an increase in [3H]thymidine greater than either agonist alone; this effect was not, however, seen when we examined changes in cell numbers. Finally, we demonstrate a mechanism whereby these responses may be downregulated: vasoactive intestinal peptide (1 microM) elevates cyclic AwMP in these cells 4. 2-fold over control and produces a dose-related inhibition of platelet-derived growth factor-driven proliferation with a maximum inhibition of 33% at 1 microM.
Jobson
T M
TM
Division of Therapeutics, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. timothy.jobson@nottingham.ac.uk
Billington
C K
CK
Hall
I P
IP
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018836:Inflammation Mediators; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II