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Neuroendocrine Modulation of IL-27 in Macrophages

Neuroendocrine Modulation of IL-27 in Macrophages

Julian Roewe, Maximilian Higer, Dennis R Riehl, Adrian Gericke, Markus P Radsak, Markus Bosmann

J Immunol. 2017 Oct 1;199(7):2503-2514.

PMID: 28835457

Abstract:

Heterodimeric IL-27 (p28/EBV-induced gene 3) is an important member of the IL-6/IL-12 cytokine family. IL-27 is predominantly synthesized by mononuclear phagocytes and exerts immunoregulatory functional activities on lymphocytic and nonlymphocytic cells during infection, autoimmunity or neoplasms. There is a great body of evidence on the bidirectional interplay between the autonomic nervous system and immune responses during inflammatory disorders, but so far IL-27 has not been defined as a part of these multifaceted neuroendocrine networks. In this study, we describe the role of catecholamines (as mediators of the sympathetic nervous system) related to IL-27 production in primary mouse macrophages. Noradrenaline and adrenaline dose-dependently suppressed the release of IL-27p28 in LPS/TLR4-activated macrophages, which was independent of α1 adrenoceptors. Instead, β2 adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The β2 adrenoceptor agonists formoterol and salbutamol mediated suppression of IL-27p28 production, when triggered by zymosan/TLR2, LPS/TLR4, or R848/TLR7/8 activation, but selectively spared the polyinosinic-polycytidylic acid/TLR3 pathway. Mechanistically, β2 adrenergic signaling reinforced an autocrine feedback loop of macrophage-derived IL-10 and this synergized with inhibition of the JNK pathway for limiting IL-27p28. The JNK inhibitors SP600125 and AEG3482 strongly decreased intracellular IL-27p28 in F4/80+CD11b+ macrophages. In endotoxic shock of C57BL/6J mice, pharmacologic activation of β2 adrenoceptors improved the severity of shock, including hypothermia and decreased circulating IL-27p28. Conversely, IL-27p28 was 2.7-fold increased by removal of the catecholamine-producing adrenal glands prior to endotoxic shock. These data suggest a novel role of the sympathetic neuroendocrine system for the modulation of IL-27-dependent acute inflammation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP63735717	AEG 3482		63735-71-7	Price

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