| First Author | Roewe J | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 7 | Pages | 2503-2514 |
| PubMed ID | 28835457 | Mgi Jnum | J:251133 |
| Mgi Id | MGI:6103436 | Doi | 10.4049/jimmunol.1700687 |
| Citation | Roewe J, et al. (2017) Neuroendocrine Modulation of IL-27 in Macrophages. J Immunol 199(7):2503-2514 |
| abstractText | 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 alpha1 adrenoceptors. Instead, beta2 adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The beta2 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, beta2 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 beta2 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. |
