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 growth factor-beta (TGF-beta) is produced in the synovial fluid of patients with rheumatoid arthritis (RA), and that TGF-beta is an important regulator in the course of the disease. Careful studies on the endogenous synthesis of TGF-beta as well as its receptors are therefore necessary to clarify the possible role of TGF-beta in RA.


METHODS
We examined the expressions of latent TGF-beta 1, -beta 2, and -beta 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 patients with RA by immunohistochemistry. Five specimens from these cases representing both active and chronic inactive stages were also examined for the corresponding mRNA by in situ hybridization. Northern blot analysis was performed on 3 synovial membranes taken from the RA patients together with a control synovium.


RESULTS
Abundant LTBP, TGF-beta 1, and TGF-beta RII-positive cells as well as less intensively stained TGF-beta 2 and TGF-beta 3-positive cells were found in the synovial 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 pattern that was similar to that demonstrated by an antibody against human dendritic cells, and also expressed HLA-DR. In situ hybridization revealed markedly increased signals for LTBP and TGF-beta RII mRNA in tissues with an active inflammatory process, when compared with tissues with less active inflammation. However, no clear differences in the levels of expression for any of the TGF-beta isoforms were found. Specimens with pronounced fibrosis, fibroblasts, and surrounding collagen fibers expressed positive immunoreactivities for all TGF-beta isoforms and LTBP. Northern blot analysis on 4 synovial tissues demonstrated positive signals for LTBP and TGF-beta 1 mRNA in all three RA patients in contrast to a normal control, which did not show any signals. An increased expression of TGF-beta RII mRNA was detected in the tissue from one of the patients.


CONCLUSIONS
An abundant expression of TGF-beta 1 and LTBP, as well as TGF-beta RII was seen in most actively proliferating synovial intimal cells, and the level of the expression varied during the course of the disease. We conclude that TGF-beta is involved tightly in the regulation of the inflammatory process, and it is thus possible that the endogenous TGF-beta functions as a self-regulator that induces the remission periods.
Taketazu
F
F
Ludwig Institute for Cancer Research, Uppsala Branch, Sweden.
Kato
M
M
Gobl
A
A
Ichijo
H
H
ten Dijke
P
P
Itoh
J
J
Kyogoku
M
M
Rönnelid
J
J
Miyazono
K
K
Heldin
C H
CH
D000595:Amino Acid Sequence; D000906:Antibodies; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D007719:Knee Joint; D053779:Latent TGF-beta Binding Proteins; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D017346:Protein Serine-Threonine Kinases; D015347:RNA Probes; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis*; D012016:Reference Values; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis*
D000906:Antibodies; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D010455:Peptides; D015347:RNA Probes; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II