Transforming growth factor beta 1 and interleukin 4 induced alpha smooth muscle actin expression and myofibroblast-like differentiation in human synovial fibroblasts in vitro: modulation by basic fibroblast growth factor.
OBJECTIVE
To discover if alpha smooth muscle actin expression and myofibroblastic differentiation are induced in synovial fibroblasts by cytokines found in the inflamed RA joint.


METHODS
Immunofluorescent microscopy and western blotting were used to examine different cultures of human synovial fibroblasts for expression of alpha actin in the presence of the cytokines transforming growth factor beta (TGF beta 1), interleukin 1 alpha (IL1 alpha), IL4, IL6, tumour necrosis factor alpha (TNF alpha), and basic fibroblast growth factor (FGF).


RESULTS
A small but significant population of cells (14.4 +/- 12.9%) expressed alpha actin under standard culture conditions. Upon treatment with TGF beta 1 there was a pronounced increase in the number of cells expressing alpha actin (68.1 +/- 5.49%), accompanied by a change in morphology to a myofibroblast-like phenotype. Other cytokines found within the inflamed joint such as IL1, TNF alpha, IL6, and basic FGF failed to induce alpha actin expression. However, IL4, which is normally absent or only present at low concentrations in the RA joint had a similar effect to TGF beta 1. It was also found that basic FGF inhibited the induction of alpha actin expression by TGF beta 1 and IL4.


CONCLUSIONS
In the presence of TGF beta 1 or IL4, fibroblasts derived from synovial tissue or synovial fluid are induced to differentiate into myofibroblast-like cells containing the alpha smooth muscle form of actin. This differentiation is inhibited by basic FGF. It is suggested that the balance between these particular cytokines may be important in the modulation of fibroblast behaviour, which could have significant effects on joint repair mechanisms and the generation of fibrous tissue within the rheumatoid joint.
Mattey
D L
DL
Staffordshire Rheumatology Centre, Burslem, Stoke on Trent.
Dawes
P T
PT
Nixon
N B
NB
Slater
H
H
D000199:Actins / Q000378:metabolism*; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000199:Actins; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D015847:Interleukin-4