Neurotransmitter modulation of interleukin 6 (IL-6) and IL-8 secretion of synovial fibroblasts in patients with rheumatoid arthritis compared to osteoarthritis

Objective. The sensory nervous system with the 2 neurotransmitters substanc e P (SP) and calcitonin gene related peptide (CGRP) is proinflammatory in e xperimental models of arthritis. The role of the sympathetic nervous system with norepinephrine (NE), adenosine, beta -endorphin, and methionine enkep halin (MENK) is not clearly understood. We studied the influence of these n eurotransmitters; on secretion of interleukin 6 (IL-6) and IL-8 in primary cultures of synovial fibroblasts of patients with rheumatoid arthritis (RA) compared to osteoarthritis (OA). Methods. Fibroblasts were isolated using fresh synovial tissue of 5 patient s with RA and 5 with OA who underwent knee joint replacement surgery. Modul ation of spontaneous secretion of IL-6 and IL-8 was investigated in vitro u sing the neurotransmitters noted above. Results. In RA fibroblasts, CGRP increased IL-6 and IL-8 secretion at 10(-1 0) to 10(-8) M (p at least < 0.01), which was not observed in OA fibroblast s. SP had no effect on either cytokine in RA fibroblasts but stimulated IL- 8 secretion at 10(-8) M in OA fibroblasts (p < 0.01). In RA fibroblasts, ad enosine and NE inhibited secretion of both cytokines at low concentrations (10(-8) M: p < 0.01). However, in OA fibroblasts there was a NE induced inc rease of IL-8 and IL-6 secretion at 10(-7) and 10(-6) M (p < 0.01), but no inhibition at lower concentrations (10(-8) M: p = NS). In RA fibroblasts. b eta -endorphin and MENK inhibited IL-8 secretion at 10(-9) to 10(-7) M (p < 0.01), whereas in OA fibroblasts the dose response curve was shifted to lo wer concentrations (10(-12) M, 10(-11) M; p < 0.01). Conclusion. In OA fibroblasts, the sympathetic neurotransmitters were stimu latory at higher concentrations. CGRP was the most potent stimulatory neuro transmitter in RA fibroblasts: whereas the sympathetic adenosine, NE, beta -endorphin. and MENK were inhibitory. This indicates a dualism of action of sympathetic and sensory neurotransmitters, with inhibitory and stimulatory effects on cytokine secretion of RA fibroblasts.