ENHANCED EXPRESSION OF TRANSFORMING GROWTH FACTOR-BETA-S AND TRANSFORMING GROWTH-FACTOR-BETA TYPE-II RECEPTOR IN THE SYNOVIAL TISSUES OF PATIENTS WITH RHEUMATOID-ARTHRITIS

BACKGROUND: A growing body of evidences suggests that transforming gro wth factor-beta (TGF-beta) is produced in the synovial fluid of patien ts with rheumatoid arthritis (RA), and that TGF-beta is an important r egulator in the course of the disease. Careful studies on the endogeno us synthesis of TGF-beta as well as its receptors are therefore necess ary to clarify the possible role of TGF-beta in RA. EXPERIMENTAL DESIG N: We examined the expressions of latent TGF-beta 1, -beta 2, and -bet a 3, the latent TGF-beta 1-binding protein (LTBP) as well as TGF-beta type II receptor (TGF-beta RII) in the synovial biopsy tissues of 21 p atients with RA by immunohistochemistry. Five specimens from these cas es representing both active and chronic inactive stages were also exam ined for the corresponding mRNA by in situ hybridization. Northern blo t analysis was performed on 3 synovial membranes taken from the RA pat ients together with a control synovium. RESULTS: Abundant LTBP, TGF-be ta 1, and TGF-beta RII-positive cells as well as less intensively stai ned TGF-beta 2 and TGF-beta 3-positive cells were found in the synovia l layer. These cells were positive for the histocompatibility antigen, HLA-DR. In lymphocyte aggregates, scattered cells positively labeled for LTBP and TGF-beta 1 were found. They stained in a reticular patter n that was similar to that demonstrated by an antibody against human d endritic cells, and also expressed HLA-DR. In situ hybridization revea led markedly increased signals for LTBP and TGF-beta RII mRNA in tissu es with an active inflammatory process, when compared with tissues wit h less active inflammation. However, no clear differences in the level s of expression for any of the TGF-beta isoforms were found. Specimens with pronounced fibrosis, fibroblasts, and surrounding collagen fiber s expressed positive immunoreactivities for all TGF-beta isoforms and LTBP. Northern blot analysis on 4 synovial tissues demonstrated positi ve signals for LTBP and TGF-beta 1 mRNA in all three RA patients in co ntrast to a normal control, which did not show any signals. An increas ed expression of TGF-beta RII mRNA was detected in the tissue from one of the patients. CONCLUSIONS: An abundant expression of TGF-beta 1 an d LTBP, as well as TGF-beta RII was seen in most actively proliferatin g synovial intimal cells, and the level of the expression varied durin g the course of the disease. We conclude that TGF-beta is involved tig htly in the regulation of the inflammatory process, and it is thus pos sible that the endogenous TGF-beta functions as a self-regulator that induces the remission periods.