Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis.
OBJECTIVE
To elucidate the role of prolactin (PRL) produced in joints as part of the pathological response of rheumatoid arthritis (RA), we studied PRL production and prolactin receptor (PRLR) expression in RA synovium and its effects on RA synovial cell functions.


METHODS
Proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells was estimated by ELISA, Western blotting analysis, and zymography. Expression of PRLR by RA synovial cells and local production of PRL were estimated by reverse transcription polymerase chain reaction and immunohistochemical staining.


RESULTS
PRL enhanced RA synovial cell proliferation. Production of proinflammatory cytokine and MMP was augmented and production of tissue inhibitor of metalloproteinases (TIMP)-1 was inhibited by PRL treatment of RA synovial cells, suggesting that PRL enhances total collagenase activity in the joints. PRLR was exclusively expressed on fibroblast-like synovial cells and lymphocytes infiltrating into the synovium in patients with RA. Both synovium infiltrating T lymphocytes and, to a lesser extent, fibroblast-like synovial cells synthesized PRL, suggesting that PRL acts as a paracrine as well as autocrine activator of RA synovial cell functions. Stimulation of synovial cells by PRL induced rapid translocation of STAT-5 from cytoplasm into nuclei of RA synovial cells, suggesting that transcriptional regulation of RA synovial cell functions by PRL affects STAT-5. Inhibitors of PRL release, such as bromocriptine, inhibited proliferation of proinflammatory cytokines and collagenases by RA synovial cells.


CONCLUSIONS
Our findings emphasize the importance of PRL, locally produced by infiltrating T lymphocytes, for aberrant synovial cell functions in RA, and suggest possible clinical application of PRL inhibitors.
Nagafuchi
H
H
Department of Immunology, St. Marianna University School of Medicine, Kanagawa, Japan.
Suzuki
N
N
Kaneko
A
A
Asai
T
T
Sakane
T
T
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D001483:Base Sequence; D015153:Blotting, Western; D001971:Bromocriptine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000008:administration & dosage / Q000096:biosynthesis*; D012016:Reference Values; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism
D019715:Tissue Inhibitor of Metalloproteinase-1; D001971:Bromocriptine; D011388:Prolactin; D019278:Matrix Metalloproteinase 3