title: Norepinephrine from synovial tyrosine hydroxylase positive cells is a strong indicator of synovial inflammation in rheumatoid arthritis.
abstract: OBJECTIVE
  Density of sympathetic nerve fibers in synovial tissue was lower in patients with rheumatoid arthritis (RA) compared to those with osteoarthritis (OA). This was accompanied by norepinephrine (NE) release from synovial tyrosine hydroxylase positive cells (TH+ cells). We investigated the role of TH+ cells and NE in synovial inflammation.
  
  
  METHODS
  Synovial tissue of 34 patients with RA and 36 with OA who underwent knee joint replacement surgery was characterized using immunohistochemistry and a synovial tissue superfusion technique, respectively. In culture experiments with mixed synoviocytes, the effect of NE on secretion of interleukin 6 (IL-6), IL-8, tumor necrosis factor (TNF), and matrix metalloproteinase-3 (MMP-3) was investigated.
  
  
  RESULTS
  Tissue density of TH+ cells was higher in RA compared to OA (63.9 vs 34.2 cells/mm2; p = 0.017). Basal NE release from synovial tissue correlated highly significantly with density of TH+ cells in RA (Rrank = 0.573, p = 0.001) but not in OA (Rrank = 0.102, NS). Basal NE release correlated with the degree of inflammation in RA (Rrank = 0.420, p = 0.021) but not in OA (Rrank = 0.174, NS), and with spontaneous IL-8 secretion in RA (Rrank = 0.581, p = 0.001) but not in OA (Rrank = 0.160, NS). Only in RA, density of TH+ cells correlated positively with spontaneous secretion of IL-6, IL-8, and MMP-3. We confirmed the extensive loss of sympathetic nerve fibers in RA compared to OA (0.32 vs 3.1 nerve fiber/mm2; p < 0.001). The ratio of sympathetic to sensory nerve fibers was 1 to 5 in RA and 2 to 1 in OA. A ratio of 1.0 separates almost all patients into 2 diseases groups (RA vs OA). Prior prednisolone treatment of RA patients was related to decreased spontaneous cytokine secretion, a lower density of T cells, CD163+ macrophages and TH+ cells, a lower degree of inflammation, and reduced synovial NE secretion. NE was able to inhibit secretion of IL-6 (in OA), IL-8 (in RA), and TNF (in RA and OA) in culture experiments.
  
  
  CONCLUSIONS
  TH+ cells and release of NE are strongly linked to a higher degree of synovial inflammation. Culture experiments indicate that NE has antiinflammatory properties at higher concentrations (10(-5) M). NE secretion of TH+ cells may be an antiinflammatory mechanism to counteract local inflammation. Thus, TH+ cell derived NE can be an important local factor of immunomodulation in synovial inflammation.
authors.affiliation: Department of Internal Medicine I, University Medical Center Regensburg, Germany.
authors.forename: Luitpold E
authors.initials: LE
authors.lastname: Miller
authors.forename: Joachim
authors.initials: J
authors.lastname: Grifka
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
mesh_terms: D000320:Adrenergic Fibers / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers; D002452:Cell Count; D002478:Cells, Cultured; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D009638:Norepinephrine / Q000032:analysis* / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology; D011237:Predictive Value of Tests; D013373:Substance P / Q000032:analysis; D013583:Synovial Membrane / Q000276:immunology / Q000294:innervation / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis*
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; D014446:Tyrosine 3-Monooxygenase; D019278:Matrix Metalloproteinase 3; D009638:Norepinephrine