Beta₂-Adrenergic Receptors Mediate the Differential Effects of Catecholamines on Cytokine Production of PBMC

Abstract

We determined characteristics of beta2-adrenergic receptors (beta2R) on peripheral blood mononuclear cells (PBMC) and cytokine production after mitogenic stimulation and coincubation with catecholamines. PBMCs were stimulated with interleukin-2 (IL-2), tetanus toxoid (TT), anti-CD3 antibody, or phytohemagglutinin (PHA). The cytokines interferon-gamma (IFN-gamma), IL-4, and IL-6 were determined by ELISA following coincubation with high-dose (10(-5) M) and low-dose (10(-9) M) epinephrine (EPI) and norepinephrine (NE). Intracellular IFN-gamma and IL-4 were studied by FACS analysis. The beta2R density was investigated using a radioligand binding assay. The stimuli induced various cytokine profiles in PBMCs. Synthesis of IFN-gamma was induced by all mitogens and could be suppressed by catecholamines (26%-85% reduction). In PHA-stimulated PBMCs, IL-4 synthesis was decreased by high-dose catecholamines (24%-28% reduction). Adding a beta-blocking agent attenuated most catecholamine effects. A highly significant negative correlation between the density of beta2R with IFN-gamma and IL-6 levels of PHA-activated PBMCs (r = -0.88 to -0.96, p < 0.01-< 0.001) was observed. The results indicate that the density of beta2R on PBMC plays a role in mediating the differential catecholamine effects on cytokine production of PBMC. Furthermore, changes in cytokine expression induced by catecholamines favor Th2 responses.

Sex differences in monocyte expression of IL-6: role of autonomic mechanisms

“…Substantial evidence in animals has found that sympathetic effector mechanisms suppress proinflammatory cytokine expression (12,21,38). Together, with these studies, the findings from the current study linking sympathovagal balance and IL-6 production in women suggest that the autonomic activity plays a role in modulating inflammatory cytokine expression.…”

“…Increases in sympathetic activity along with ␤-adrenergic receptor activation suppress stimulated production of proinflammatory cytokines (12,21,38). Substantial evidence indicates that autonomic nervous system activity differs between men and women, in which men show higher levels of sympathetic balance than women (3,19,22,35).…”

Hostility, anger, and depression predict increases in C3 over a 10-year period

“…Although sympathetic activation has been associated with reduced stimulated production of proinflammatory cytokines (Watkins, et al, 1999), this is not always the case. For example, evidence suggests that beta-adrenergic receptor density mediates the effects of catecholamines on cytokine production (Wahle, et al, 2005) with norepinephrine inducing cytokine production in mononuclear cells exhibiting lower betaadrenergic receptor density. Those findings led us to hypothesize that stress-induced adrenergic activity, in the presence of down-regulated beta-receptors, leads to C3 production via activation of transcription factors and proinflammatory cytokines.…”

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

“…Peripheral blood mononuclear cells (PBMCs), specifically monocytes, B cells and CD8 + T cells, from RA patients express lower levels of β2-ARs compared with healthy subjects (25) and the receptor density on RA synovial fluid lymphocytes is even less (26). RA PBMCs therefore also are less responsive to NE treatment compared with healthy subjects: upon NE administration in vitro (25,27) they are less effective in suppressing T-cell activation and proliferation, and the stimulated cytokine response was not decreased as much. In active systemic and polyarticular juvenile RA there is a diminished cAMP production upon β2-AR stimulation, indicating a defective neuroimmune response (28).…”