Research article

Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis

Matthias Wahle¹ , Gesine Hanefeld¹ , Stephan Brunn¹ , Rainer H Straub² , Ulf Wagner¹ , Andreas Krause³ , Holm Häntzschel¹ and Christoph GO Baerwald¹

¹Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany

²Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany

³Immanuel Hospital, Rheumatology Clinic, Königstrasse 63, 14109 Berlin, Germany

author email corresponding author email

Arthritis Research & Therapy 2006, 8:R138doi:10.1186/ar2028

Published:	6 August 2006

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)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-γ 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-γ, TNF-α, and IL-10 at a concentration of 10^-5 M. In addition, IFN-γ 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-γ 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-γ 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-γ 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.