Alcohol alters IL-6 Signal Transduction in the CNS of Transgenic Mice with Increased Astrocyte Expression of IL-6
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ORIGINAL RESEARCH
Alcohol alters IL‑6 Signal Transduction in the CNS of Transgenic Mice with Increased Astrocyte Expression of IL‑6 Donna L. Gruol1 · Claudia Melkonian1 · Salvador Huitron‑Resendiz2 · Amanda J. Roberts2 Received: 20 February 2020 / Accepted: 15 May 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Neuroimmune factors, including the cytokine interleukin-6 (IL-6), are important chemical regulators of central nervous system (CNS) function under both physiological and pathological conditions. Elevated expression of IL-6 occurs in the CNS in a variety of disorders associated with altered CNS function, including excessive alcohol use. Alcohol-induced production of IL-6 has been reported for several CNS regions including the cerebellum. Cerebellar actions of alcohol occur through a variety of mechanisms, but alcohol-induced changes in signal transduction, transcription, and translation are known to play important roles. IL-6 is an activator of signal transduction that regulates gene expression. Thus, alcohol-induced IL-6 production could contribute to cerebellar effects of alcohol by altering gene expression, especially under conditions of chronic alcohol abuse, where IL-6 levels could be habitually elevated. To gain an understanding of the effects of alcohol on IL-6 signal transduction, we studied activation/expression of IL-6 signal transduction partners STAT3 (Signal Transducer and Activator of Transcription), CCAAT-enhancer binding protein (C/EBP) beta, and p42/p44 mitogen-activated protein kinase (MAPK) at the protein level. Cerebella of transgenic mice that express elevated levels of astrocyte produced IL-6 in the CNS were studied. Results show that the both IL-6 and chronic intermittent alcohol exposure/withdrawal affect IL-6 signal transduction partners and that the actions of IL-6 and alcohol interact to alter activation/expression of IL-6 signal transduction partners. The alcohol/IL-6 interactions may contribute to cerebellar actions of alcohol, whereas the effects of IL-6 alone may have relevance to cerebellar changes occurring in CNS disorders associated with elevated levels of IL-6. Keywords STAT3 · C/EPB beta · p42/44 MAPK · Glia · GFAP · Chronic intermittent alcohol
Introduction Alcohol exposure results in elevated CNS expression of a variety of neuroimmune factors including the cytokine IL-6 (Kane et al. 2013, 2014; Doremus-Fitzwater et al. 2014,2015; Alfonso-Loeches et al. 2010; Lippai et al. 2013; Roberts et al. 2019; Robinson et al. 2014), a cytokine known to be increased in the serum of alcoholics (Nicolaou et al. 2004; Heberlein et al. 2014). Alcohol-induced expression of neuroimmune factors has been shown to vary with CNS region, age, alcohol dose, and previous alcohol experience * Donna L. Gruol [email protected] 1
Neuroscience Department, SR301, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Animal Models Core Facility, The Scripps Research Institute, La Jolla, CA 92037, USA
2
(Kane et al. 201
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