title: Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro.
abstract: Corticosteroids (CS) and norepinephrine (NE) support each other's biological effects. Thus, deficiency of cortisol and reduced synovial sympathetic innervation (SSI) may be proinflammatory in rheumatoid arthritis (RA). This study tested the anti-inflammatory cooperativity of CS and NE in human RA synovial tissue. In an in vivo study, 32 patients with RA (with prior CS therapy/without SSI: n=7; without prior CS therapy/with SSI: 6; with prior CS therapy/with SSI: 19) were investigated for synovial inflammation. In an in vitro study with synoviocytes from RA and OA patients, the separate and combined effects of cortisol and NE were studied. In the in vivo study, patients with prior CS therapy/with SSI showed lower secretion of synovial IL-8 than the other groups, lower synovial density of T cells and macrophages, and lower overall inflammation. In the in vitro study, a cooperative suppressive effect of NE (10(-6) M to 10(-8) M) and cortisol (10(-6) M and 10(-7) M) on secretion of IL-8 and TNF from primary early culture mixed RA synoviocytes was observed. This cooperative effect was not observed in OA synoviocytes. In the same RA and OA patients, the cooperative effect was lost in 3rd passage synovial fibroblasts. This study demonstrates the cooperativity of cortisol and NE for inhibition of proinflammatory mediators produced in the synovial tissue of RA patients. These results underscore that coupling of an efficient secretion of systemic cortisol together with local production of NE is important in order to lower synovial inflammation.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine I, University Hospital, Regensburg, Germany. rainer.straub@klinik.uni-r.de
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.forename: Christian
authors.initials: C
authors.lastname: Günzler
authors.forename: Luitpold E
authors.initials: LE
authors.lastname: Miller
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cutolo
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Stefan
authors.initials: S
authors.lastname: Schill
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D009638:Norepinephrine / Q000494:pharmacology*; D010003:Osteoarthritis / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology; D013564:Sympathetic Nervous System / Q000737:chemistry; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000294:innervation
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D019278:Matrix Metalloproteinase 3; D006854:Hydrocortisone; D009638:Norepinephrine