Proinflammatory alpha-Adrenergic Neuronal Regulation of Splenic IFN-gamma, IL-6, and TGF-beta of Mice from Day 15 onwards in Arthritis

摘要

Introduction:In arthritic mice, a sympathetic influence is proinflammatory from the time point of immunization until the onset of disease (days 0-32), but reasons are unknown. Disruption of the major anti-inflammatory pathway through G(alpha s)-coupled receptors probably play a role. For example, noradrenaline cannot operate via anti-inflammatory beta(2)-adrenoceptors but through proinflammatory alpha(1/2)-ad-renoceptors. This might happen, first, through a loss of sympathetic nerve fibers in inflamed tissue with low neurotransmitter levels (noradrenaline only binds to high-affinity alpha-adrenoceptors) and, second, through an alteration in G-protein receptor coupling with a predominance of alpha-adrenergic signaling. We hypothesized that both mechanisms play a role in the course of collagen type II-induced arthritis (CIA) in the spleen in mice.Methods:In CIA mice, nerve fiber density in the spleen was quantified by immunohistochemistry techniques. The functional impact of sympathetic nerve fibers in the spleen was studied by a micro-superfusion technique of spleen slices with a focus on the secretion of IFN-gamma and IL-6 (proinflammatory) and TGF-beta (anti-inflammatory).Results:During CIA, sympathetic nerve fibers get increasingly lost from day14 until day 55 after immunization. The influence of electrically released noradrenaline diminishes in the course of arthritis. At all investigated time points (days 14, 32, and 55), only proinflammatory neuronal alpha-adrenergic effects on cytokine secretion were demonstrated (i.e., stimulation of IFN-gamma and IL-6 and inhibition of TGF-beta).Conclusion:Sympathetic nerve fibers are rapidly lost in the spleen, and only proinflammatory alpha-adrenergic neuronal regulation of cytokine secretion takes place throughout the course of arthritis. These results support a predominance of a proinflammatory alpha-adrenergic sympathetic influence in arthritis.