title: Neurotransmitter modulation of interleukin 6 (IL-6) and IL-8 secretion of synovial fibroblasts in patients with rheumatoid arthritis compared to osteoarthritis.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine I, University Medical Center Regensburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Raap
authors.forename: H P
authors.initials: HP
authors.lastname: Jüsten
authors.forename: L E
authors.initials: LE
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Cutolo
authors.forename: J
authors.initials: J
authors.lastname: Schölmerich
authors.forename: R H
authors.initials: RH
authors.lastname: Straub
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008875:Middle Aged; D009475:Neurons, Afferent / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D013564:Sympathetic Nervous System / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D018377:Neurotransmitter Agents