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The Cytokine m RNA Increase Induced by Withdrawal from Chronic Ethanol in the Sterile Environment of Brain is Mediated by CRF and HMGB 1 Release
Author(s) -
Whitman Buddy A.,
Knapp Darin J.,
Werner David F.,
Crews Fulton T.,
Breese George R.
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12189
Subject(s) - chapel , history , art history
Background Many neurobiological factors may initiate and sustain alcoholism. Recently, dysregulation of the neuroimmune system by chronic ethanol ( CE ) has implicated Toll‐like receptor 4 ( TLR 4) activation. Even though TLR 4s are linked to CE initiation of brain cytokine m RNA s, the means by which CE influences neuroimmune signaling in brain in the absence of infection remains uncertain. Therefore, the hypothesis is tested that release of an endogenous TLR 4 agonist, high‐mobility group box 1 ( HMGB 1) and/or corticotropin‐releasing factor ( CRF ) during CE withdrawal are responsible for CE protocols increasing cytokine m RNA s. Methods Acute ethanol (EtOH; 2.75 g/kg) and acute lipopolysaccharide ( LPS ; 250 μg/kg) dosing on cytokine m RNA s are first compared. Then, the effects of chronic LPS exposure (250 μg/kg for 10 days) on cytokine m RNA s are compared with changes induced by CE protocols (15 days of continuous 7% EtOH diet [ CE protocol] or 3 intermittent 5‐day cycles of 7% EtOH diet [ CIE protocol]). Additionally, TLR 4, HMGB 1, and downstream effector m RNA s are assessed after CE , CIE , and chronic LPS . To test whether HMGB 1 and/or CRF support the CE withdrawal increase in cytokine m RNA s, the HMGB 1 antagonists, glycyrrhizin and ethyl pyruvate, and a CRF 1 receptor antagonist ( CRF 1 RA ) are administered during 24 hours of CE withdrawal. Results While cytokine m RNA s were not increased following acute EtOH, acute LPS increased all cytokine m RNA s 4 hours after injection. CE produced no change in cytokine m RNA s prior to CE removal; however, the CE and CIE protocols increased cytokine m RNA s by 24 hours after withdrawal. In contrast, chronic LPS produced no cytokine m RNA changes 24 hours after LPS dosing. TLR 4 m RNA was elevated 24 hours following both CE protocols and chronic LPS exposure. While chronic LPS had no effect on HMGB 1 m RNA , withdrawal from CE protocols significantly elevated HMGB 1 m RNA . Systemic administration of HMGB 1 antagonists or a CRF 1 RA significantly reduced the cytokine m RNA increase following CE withdrawal. The CRF 1 RA and the HMGB 1 antagonist, ethyl pyruvate, also reduced the HMGB 1 m RNA increase that followed CE withdrawal. Conclusions By blocking HMGB 1 or CRF action during CE withdrawal, evidence is provided that HMGB 1 and CRF release are critical for the CE withdrawal induction of selected brain cytokine m RNA s. Consequently, these results clarify a means by which withdrawal from CE exposure activates neuroimmune function in the sterile milieu of brain.