Altered Expression of Cytokine Signaling Pathway Genes in Peripheral Blood Cells of Alcohol Dependent Subjects: Preliminary Findings

Abstract

Background Pre-clinical and clinical studies have implicated changes in cytokine and innate immune gene-expression in both the development of and end-organ damage resulting from alcohol dependence. However, these changes have not been systematically assessed on the basis of alcohol consumption in human subjects. Methods Illumina Sentrix Beadchip (Human-6v2) microarrays were used to measure levels of gene-expression in peripheral blood in 3 groups of subjects: those with alcohol dependence (AD, n=12), heavy drinkers (HD, defined as regular alcohol use over the past year of at least 8 standard drinks/week for women and at least 15 standard drinks/week for men, n=13), and moderate drinkers (MD, defined as up to 7 standard drinks/week for women and 14 standard drinks/week for men, n=17). Results 436 genes were differentially expressed among the three groups of subjects (FDR corrected p-value < 0.05). 291 genes differed between AD and MD subjects, 240 differed between AD and HD subjects, but only 6 differed between HD and MD subjects. Pathway analysis using DAVID and GeneGO Metacore software showed that the most affected pathways were those related to T-cell receptor and JAK-Stat (Janus kinase-Signal transducer and activator of transcription) signaling. Conclusions These results suggest the transition from heavy alcohol use to dependence is accompanied by changes in the expression of genes involved in regulation of the innate immune response. Such changes may underlie some of the previously described changes in immune function associated with chronic alcohol abuse. Early detection of these changes may allow individuals at high risk for dependence to be identified.

Stress‐Related Alcohol Consumption in Heavy Drinkers Correlates with Expression of miR‐10a, miR‐21, and Components of the TAR‐RNA‐Binding Protein‐Associated Complex

“…However, little, if any, information is available regarding how such changes may influence drinking behavior in human subjects. In a previous study, we demonstrated alterations in the expression of multiple stress-related genes in the peripheral blood of subjects with alcohol dependence compared to either heavy or moderate drinkers (Beech et al, 2012). However, since gene-expression was analyzed at only a single time-point, we were unable to determine the relationship of these changes to drinking behavior.…”

Opposing effects of alcohol on the immune system

“…Alcohol-induced alterations in gene expression involved in cytokine signaling pathways were examined in male and female subjects with alcohol dependence (AD; more than 25 drinks/week prior to study; n=10), heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 drinks/week for women and at least 15 drinks/week for me; n=13), and moderate drinkers (MD; defined as up to 7 drinks/week for women and 14 drinks/week for men; n=17). After normalization, 436 differentially expressed genes in blood samples were identified: 291 genes differed between AD and MD subjects, 240 between AD and HD subjects, but only 6 differed between HD and MD subjects (Beech, Qu et al 2012). Many of the differentially expressed genes were involved in the regulation of the immune response by cytokine signaling and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway.…”

“…Many of the differentially expressed genes were involved in the regulation of the immune response by cytokine signaling and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway. Expression of interferon receptor 2 (IFNAR2) was down-regulated in HD subjects compared to MD subjects which could contribute to deficits in both innate and adaptive immunity (Beech, Qu et al 2012). IL-15, a cytokine critical for promoting survival, proliferation, and activation of NK and CD8 T cells, was found to be up-regulated in AD subjects but there was no difference between HD and MD subjects (Beech, Qu et al 2012).…”

“…Expression of interferon receptor 2 (IFNAR2) was down-regulated in HD subjects compared to MD subjects which could contribute to deficits in both innate and adaptive immunity (Beech, Qu et al 2012). IL-15, a cytokine critical for promoting survival, proliferation, and activation of NK and CD8 T cells, was found to be up-regulated in AD subjects but there was no difference between HD and MD subjects (Beech, Qu et al 2012). Expression of the receptor for IL-21, which has been reported in autoimmune diseases, was found to be up-regulated in AD subjects (Beech, Qu et al 2012).…”

“…IL-15, a cytokine critical for promoting survival, proliferation, and activation of NK and CD8 T cells, was found to be up-regulated in AD subjects but there was no difference between HD and MD subjects (Beech, Qu et al 2012). Expression of the receptor for IL-21, which has been reported in autoimmune diseases, was found to be up-regulated in AD subjects (Beech, Qu et al 2012). …”