Abstract
Alcohol differentially affects human health, depending on the pattern of exposure. Moderate intake provides beneficial mood modulation and an anti-inflammatory effect, while excessive consumption leads to immunosuppression and various alcohol use disorders. The mechanism underlying this bi-phasic action mode of alcohol has not been clearly defined. Our previous publication demonstrated that ethanol, in the absence of glucocorticoids (GCs), induces expression of Glucocorticoid-Induced Leucine Zipper (GILZ), a key molecule that transduces GC anti-inflammatory effect through a non-canonical activation of glucocorticoid receptor (1). Here we report that similar short-chain alcohols, such as ethanol, propanol and isopropanol, share the same property of upregulating GILZ gene expression, and blunt cell inflammatory response in vitro. When mice were exposed to these alcohols, GILZ gene expression in immune cells was augmented in a dose-dependent manner. Monocytes and neutrophils were most affected. The short-chain alcohols suppressed host inflammatory response to lipopolysaccharide (LPS) and significantly reduced LPS-induced mortality. Intriguingly, propanol and isopropanol displayed more potent protection than ethanol at the same dose. Inhibition of ethanol metabolism enhanced the ethanol protective effect, suggesting that it is ethanol, not its derivatives or metabolites, that induces immune suppression. Taken together, short-chain alcohols per se upregulate GILZ gene expression and provide immune protection against LPS toxicity, suggesting a potential measure to counter LPS septic shock in a resource limited situation.
Highlights
An alcohol is any organic compound in which a hydroxyl group (−OH) is bound to a carbon atom of an alkyl or substituted alkyl group
Our previous studies demonstrated that ethanol upregulates Glucocorticoid-Induced Leucine Zipper (GILZ) gene expression and suppresses LPS-elicited inflammatory response in human airway epithelial cells and MM6 cells [1, 42]
Propanol, and isopropanol are all short-chain alcohols with a similar molecular structure, we predicted that they share the same property in regulating GILZ expression and cell inflammatory response
Summary
An alcohol is any organic compound in which a hydroxyl group (−OH) is bound to a carbon atom of an alkyl or substituted alkyl group. Acute ethanol exposure reduces lipopolysaccharide (LPS)-induced inflammatory response in vivo [16, 17] and protects mice against staphylococcal enterotoxin B [18, 19]. Related to the current alcohol study, our and others’ research indicated that ethanol activates GR signaling in the absence of GCs [42, 43]. We hypothesized that if ethanol prompts GR-GILZ signaling non-canonically, other short-chain alcohols should share the same effect. To test this hypothesis, we compared ethanol, propanol and isopropanol in their modulation of GILZ expression and their effect on host protection against LPS septic immune response
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