The pathogenic role of prolactin in patients with rheumatoid arthritis

Abstract

Defects in the hypothalamus-pituitary-adrenal axis have been observed in patients with rheumatoid arthritis (RA). Prolactin (PRL) levels are often elevated in patients with RA. To elucidate roles of PRL in the pathological responses occurring within the affected joints in patients with RA, we have studied PRL production and PRL receptor (PRLR) expression in RA synovium and its effects on RA synovial cell functions. We found the accumulation of PRL producing lymphocytes and PRLR bearing synovial cells in RA synovial tissue. We also found that in vitro treatment with PRL induces enhanced proliferation of RA synovial cells. PRL treatment provoked excessive production of proinflammatory cytokines and of the tissue destructive proteolytic enzyme, matrix metalloproteinase (MMP), by RA synovial cells. In addition, PRL inhibited tissue inhibitor of metalloproteinase (TIMP)-1 production by the synovial cells. Thus, total collagenase activity in the joints may be upregulated in case of excessive PRL secretion 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 fibroblast like synovial cells synthesized PRL, suggesting that PRL acts as a paracrine as well as autocrine activator of RA synovial cell functions. Stimulation by PRL of synovial cells induced rapid translocation of signal transduction and activation of transcription (STAT)-5 from cytoplasm into nuclei of RA synovial cells, suggesting transcriptional regulation involving STAT-5 by PRL of RA synovial cell functions. Bromocriptine (BCR), an inhibitor of PRL release, inhibited proliferation of RA synovial cells. BCR inhibited proinflammatory cytokine and collagenase production by RA synovial cells. We want to emphasize the importance of locally produced PRL by infiltrating T lymphocytes in the induction of aberrant synovial cell functions in patients with RA.