The sensory nervous system with the 2 neurotransmitters substance P (SP) and calcitonin gene related peptide (CGRP) is proinflammatory in experimental models of arthritis. The role of the sympathetic nervous system with norepinephrine (NE), adenosine, beta-endorphin, and methionine enkephalin (MENK) is not clearly understood. We studied the influence of these neurotransmitters 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).
Fibroblasts were isolated using fresh synovial tissue of 5 patients with RA and 5 with OA who underwent knee joint replacement surgery. Modulation of spontaneous secretion of IL-6 and IL-8 was investigated in vitro using the neurotransmitters noted above.
In RA fibroblasts, CGRP increased IL-6 and IL-8 secretion at 10(-10) to 10(-8) M (p at least < 0.01), which was not observed in OA fibroblasts. 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, adenosine 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 increase 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, beta-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 lower concentrations (10(-12) M, 10(-11) M; p < 0.01).
In OA fibroblasts, the sympathetic neurotransmitters were stimulatory at higher concentrations. CGRP was the most potent stimulatory neurotransmitter 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.