Evidence for neural regulation of inflammatory synovial cell functions by secreting calcitonin gene-related peptide and vasoactive intestinal peptide in patients with rheumatoid arthritis

OBJECTIVE: To elucidate the possible involvement of the nervous system in the regulation of pathophysiologic responses in patients with rheumatoid arthritis (RA), we examined the expression of peripheral nerves containing the neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in RA synovium and their effects on RA synovial cell functions. METHODS: The effects of CGRP and VIP on proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells were estimated by enzyme-linked immunosorbent assay, and their messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilutions of the complementary DNA. Expression of CGRP receptors (CGRPRs) and VIP receptors (VIPRs) on RA synovial cells was assessed by RT-PCR and radioreceptor assays. The functions of CGRPRs and VIPRs of the synovial cells were studied by using a CGRPR antagonist and a VIPR antagonist, respectively. RESULTS: CGRP and VIP inhibited the proliferation of, and the proinflammatory cytokine and MMP production by, RA synovial cells at the level of mRNA expression. Expression of CGRPR and VIPR on RA fibroblast-like synovial cells was confirmed by RT-PCR and radioreceptor assays. Functions of the neuropeptide receptors were inhibited by their receptor antagonists. CGRP and VIP inhibited nuclear translocation and phosphorylation of the transcription factor cAMP response element binding protein in RA synovial cells. CONCLUSION: CGRP and VIP inhibited excessive synovial cell functions, which suggests neural regulation of inflammatory responses in patients with RA and possible clinical application of the neuropeptides.