Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence

• Published in: Addiction biology Vol. 22; no. 6; pp. 1829 - 1841
• Main Authors: Pascual, María, Montesinos, Jorge, Marcos, Miguel, Torres, Jorge‐Luis, Costa‐Alba, Pilar, García‐García, Francisco, Laso, Francisco‐Javier, Guerri, Consuelo
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-11-2017
• Subjects: Adolescent; Adolescent humans; adolescent mice; Adolescents; Adult; Alcohol; Animals; Binge Drinking - blood; Binge Drinking - metabolism; Brain - drug effects; Brain - metabolism; Central Nervous System Depressants - blood; Central Nervous System Depressants - pharmacology; Chemokines; Chemokines - blood; Chemokines - metabolism; Child development; Cognitive ability; Colony-stimulating factor; Cytokines; Cytokines - blood; Cytokines - metabolism; Disease Models, Animal; Drinking behavior; Ethanol; Ethanol - blood; Ethanol - pharmacology; Female; Fractalkine; gender difference; Gender differences; Humans; Immune system; Inflammation; Interleukin 1; Interleukin 2; Interleukin 4; Interleukin 6; Interleukin 8; Intoxication; Macrophage inflammatory protein; Macrophage inflammatory protein 1; Macrophages; Male; Males; Mice; Mice, Knockout; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; mRNA; Plasma levels; Polymerase Chain Reaction; Prefrontal cortex; Rodents; Sex differences; Sex Factors; Spain; TLR4; TLR4 protein; Toll-like receptors; Underage Drinking; Young Adult; adolescent mice; gender difference; Adolescent humans; inflammation; TLR4
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12461

Heavy binge drinking in adolescence can cause long‐term cognitive and behavioral dysfunctions. Recent experimental evidence indicates the participation of immune system activation in the effects of ethanol in the adolescent brain and suggests gender differences. The present study aims to assess plasma cytokine and chemokine levels in male and female adolescents and young adults during acute alcohol intoxication and to correlate these results with the toll‐like receptor 4 (TLR4) response. The potential role of the TLR4 signaling response was also assessed in plasma and prefrontal cortex (PFC) of adolescent wild‐type and TLR4‐knockout male and female mice with binge ethanol treatment. The results showed that alcohol intoxication increased the plasma levels of several cytokine and chemokine [interferon‐γ, interleukin (IL)‐10, IL‐17A, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, fractalkine, monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1α (MIP‐1α)] and the upregulation of TLR4 mRNA levels occurred in intoxicated females, while elevation of colony‐stimulating factor was only observed in the plasma of males. In wild‐type female adolescent mice, intermittent ethanol treatment increased the levels of several cytokines (IL‐17A and IL‐1β) and chemokines (MCP‐1, MIP‐1α and fractalkine) in PFC and in serum (IL‐17A, MCP‐1 and MIP‐1α), but significant differences in the fractalkine levels in PFC were observed only in male mice. No changes in serum or prefrontal cortex cytokine and chemokine levels were noted in ethanol‐treated male or female TLR4‐knockout mice. Our findings revealed that females are more vulnerable than males to inflammatory effects of binge ethanol drinking and suggested that TLR4 is an important target of ethanol‐induced inflammation and neuroinflammation in adolescence.
Female adolescents are more vulnerable than male adolescents to the inflammatory effects of binge alcohol drinking. Circulating cytokines and chemokines might serve as clinical biomarkers of neuroinflammation. The TLR4 response is an important target of the ethanol‐induced immune and neuroimmune response in adolescence. This figure shows a negative correlation (Pearson's coefficient) between cytokines/chemokines and blood alcohol levels in intoxicated females (red ellipses) and positive correlation in intoxicated males (blue ellipses). Black and white points denote significance and tendency, respectively.