Sympathetic inhibition of IL-6, IFN-γ, and KC/CXCL1 and sympathetic stimulation of TGF-β in spleen of early arthritic mice

ObjectivesThe connection between sympathetic nerve fibers and immune cells in the spleen is known. In the context of arthritis, the functional meaning of the neuroimmune contact remains unclear. From immunization until disease outbreak, the sympathetic nervous system (SNS) has a proinflammatory influence which is converted into an anti-inflammatory influence after disease outbreak. This study investigated the influence of neuronally released neurotransmitters on IFN-γ, KC (CXCL1), IL-6, and TGF-β in spleen of mice shortly after outbreak of collagen type II-induced arthritis.MethodsSpleens were removed when animals reached an arthritis score of 3 on a scale of 1–16 (approx. on day 32) in order to generate 0.35 mm-thick spleen slices. Spleen slices were transferred to superfusion microchambers in order to electrically induce release of sympathetic neurotransmitters. By means of this technique, the effect of physiologically released neurotransmitters was investigated on secretion of IFN-γ, KC, IL-6, and TGF-β.ResultsHigh amounts of IFN-γ, KC, IL-6, and TGF-β were released from superfused spleen, and electrical stimulation markedly inhibited IFN-γ, KC, and IL-6 release but pronouncedly stimulated TGF-β. The adrenergic influence via β-adrenoceptors stimulated release of IL-6 and, particularly, TGF-β. However, catecholamines inhibit release of IL-6 via α1-adrenergic pathways but without any effect on TGF-β. The co-transmitter adenosine stimulated IL-6 release via A1-adenosine receptors but no influence was recognized on TGF-β.ConclusionAt disease outbreak, electrically released endogenous neurotransmitters of the SNS inhibit IFN-γ, KC, and IL-6 but β-adrenergically stimulate TGF-β. This creates an anti-inflammatory milieu that might be responsible for the observed dual influence of the SNS on arthritis.

Highlight
► In early arthritis, studying neuroimmune communication in superfused spleen slices revealed that TGF-β is strongly increased by local sympathetic β-adrenergic pathways.