title: Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis.
abstract: To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5) M to 10(-11) M. Interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-gamma and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-gamma, TNF-alpha, and IL-10 at a concentration of 10(-5) M. In addition, IFN-gamma release was suppressed by 10(-7) M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5) M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-gamma production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-gamma production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-gamma production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.
authors.affiliation: Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany. matthias.wahle@kgu.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Wahle
authors.forename: Gesine
authors.initials: G
authors.lastname: Hanefeld
authors.forename: Stephan
authors.initials: S
authors.lastname: Brunn
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.forename: Holm
authors.initials: H
authors.lastname: Häntzschel
authors.forename: Christoph G O
authors.initials: CG
authors.lastname: Baerwald
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; C508598:IL4 protein, human; D018343:Receptors, Adrenergic, beta-2; D013566:Sympathomimetics; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000242:Cyclic AMP; D009638:Norepinephrine; D004837:Epinephrine