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Immune function genes, genetics, and the neurobiology of addiction.

Crews FT - Alcohol Res (2012)

Bottom Line: Likewise, altered neuroimmune signaling processes are linked to alcohol-induced negative affect and depression-like behaviors and also regulate alcohol-drinking behavior.Moreover, the expression of several genes and proteins involved in innate immunity is enhanced in addicted people.Finally, specific variants of multiple innate immune genes are associated with the genetic risk for alcoholism in humans, further strengthening the connection between increased brain innate immune gene expression and alcohol addiction.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

ABSTRACT
The neuroimmune system (i.e., the immune system and those components of the nervous system that help regulate immune responses), and in particular the innate immune system, play a role in the development of addictions, including alcoholism, particularly in the context of stressful situations. Certain cells of the neuroimmune system are activated both by stress and by environmental factors such as alcohol, resulting in the induction of genes involved in innate immunity. One of the molecules mediating this gene induction is a regulatory protein called nuclear factor-κB, which activates many innate immune genes. Innate immune gene induction in certain brain regions (e.g., the frontal cortex), in turn, can disrupt decision making, which is a characteristic of addiction to alcohol and other drugs. Likewise, altered neuroimmune signaling processes are linked to alcohol-induced negative affect and depression-like behaviors and also regulate alcohol-drinking behavior. Moreover, the expression of several genes and proteins involved in innate immunity is enhanced in addicted people. Finally, specific variants of multiple innate immune genes are associated with the genetic risk for alcoholism in humans, further strengthening the connection between increased brain innate immune gene expression and alcohol addiction.

No MeSH data available.


Related in: MedlinePlus

Innate immune gene polymorphisms associated with risk for alcoholism. The schematic shows a representative astrocyte or microglial cell. Genes associated with genetic risk for alcoholism are in light blue. Nuclear factor κ-lightchain–enhancer of activated B cells (NF-κB) is a key transcription factor involved in induction of innate immune genes that is sensitive to reactive oxygen species (ROS). These ROS are generated by the enzyme CYP2E1 during alcohol metabolism, and certain DNA sequences (i.e., polymorphisms) in the CYP2E1 gene are associated with alcoholism. CYP2E1 is highly expressed in monocyte-like cells, which are activated when CYP2E1 metabolizes alcohol. The ROS formed during this process activate proinflammatory NF-κB responses. Chronic ethanol treatment increases CYP2E1 expression in the brain, particularly in astrocytes.The resulting elevated ROS levels activate NF-κB–mediated transcription of innate immune genes, and this response may be amplified in the presence of certain NF-κB polymorphisms (i.e., NF-κB1). Certain variants of other genes also are associated with alcoholism, including polymorphisms of T NFα, interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), and other components of the IL-1 gene complex, as well as of certain proteins in the space surrounding the cells (i.e., extracellular matrix proteins [ECM]).
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f3-arcr-34-3-355: Innate immune gene polymorphisms associated with risk for alcoholism. The schematic shows a representative astrocyte or microglial cell. Genes associated with genetic risk for alcoholism are in light blue. Nuclear factor κ-lightchain–enhancer of activated B cells (NF-κB) is a key transcription factor involved in induction of innate immune genes that is sensitive to reactive oxygen species (ROS). These ROS are generated by the enzyme CYP2E1 during alcohol metabolism, and certain DNA sequences (i.e., polymorphisms) in the CYP2E1 gene are associated with alcoholism. CYP2E1 is highly expressed in monocyte-like cells, which are activated when CYP2E1 metabolizes alcohol. The ROS formed during this process activate proinflammatory NF-κB responses. Chronic ethanol treatment increases CYP2E1 expression in the brain, particularly in astrocytes.The resulting elevated ROS levels activate NF-κB–mediated transcription of innate immune genes, and this response may be amplified in the presence of certain NF-κB polymorphisms (i.e., NF-κB1). Certain variants of other genes also are associated with alcoholism, including polymorphisms of T NFα, interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), and other components of the IL-1 gene complex, as well as of certain proteins in the space surrounding the cells (i.e., extracellular matrix proteins [ECM]).

Mentions: Stress and AODs, as well as sensory and hormonal signals, activate a regulatory protein (i.e., transcription factor3) called nuclear factor κ–light-chain enhancer of activated B cells (NF-κB) that is produced in large amounts (i.e., is highly expressed) in monocytes and microglia. Although NF-κB is found in most cells, it is the key transcription factor involved in the induction of innate immune genes in microglia and other monocyte-like cells. A wide range of stimuli, such as stress, cytokines, oxidative free radicals, ultraviolet irradiation, bacterial or viral molecules, and many other signaling molecules, increase binding of NF-κB to specific sequences of the DNA. This binding increases the transcription of many genes, particularly those encoding signaling molecules (e.g., chemokines and cytokines) and enzymes (e.g., oxidases and proteases) (figure 3). Studies found that ethanol can increase the binding of NF-κB to its corresponding DNA sequences both in the brains of living organisms (Crews et al. 2006) and in cultured brain slices obtained from a brain area called the hippocampal–entorhinal cortex (HEC) (Zou and Crews 2006). These and other studies also have indicated that ethanol increases transcription of NF-κB target genes, including the genes encoding the following:


Immune function genes, genetics, and the neurobiology of addiction.

Crews FT - Alcohol Res (2012)

Innate immune gene polymorphisms associated with risk for alcoholism. The schematic shows a representative astrocyte or microglial cell. Genes associated with genetic risk for alcoholism are in light blue. Nuclear factor κ-lightchain–enhancer of activated B cells (NF-κB) is a key transcription factor involved in induction of innate immune genes that is sensitive to reactive oxygen species (ROS). These ROS are generated by the enzyme CYP2E1 during alcohol metabolism, and certain DNA sequences (i.e., polymorphisms) in the CYP2E1 gene are associated with alcoholism. CYP2E1 is highly expressed in monocyte-like cells, which are activated when CYP2E1 metabolizes alcohol. The ROS formed during this process activate proinflammatory NF-κB responses. Chronic ethanol treatment increases CYP2E1 expression in the brain, particularly in astrocytes.The resulting elevated ROS levels activate NF-κB–mediated transcription of innate immune genes, and this response may be amplified in the presence of certain NF-κB polymorphisms (i.e., NF-κB1). Certain variants of other genes also are associated with alcoholism, including polymorphisms of T NFα, interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), and other components of the IL-1 gene complex, as well as of certain proteins in the space surrounding the cells (i.e., extracellular matrix proteins [ECM]).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860409&req=5

f3-arcr-34-3-355: Innate immune gene polymorphisms associated with risk for alcoholism. The schematic shows a representative astrocyte or microglial cell. Genes associated with genetic risk for alcoholism are in light blue. Nuclear factor κ-lightchain–enhancer of activated B cells (NF-κB) is a key transcription factor involved in induction of innate immune genes that is sensitive to reactive oxygen species (ROS). These ROS are generated by the enzyme CYP2E1 during alcohol metabolism, and certain DNA sequences (i.e., polymorphisms) in the CYP2E1 gene are associated with alcoholism. CYP2E1 is highly expressed in monocyte-like cells, which are activated when CYP2E1 metabolizes alcohol. The ROS formed during this process activate proinflammatory NF-κB responses. Chronic ethanol treatment increases CYP2E1 expression in the brain, particularly in astrocytes.The resulting elevated ROS levels activate NF-κB–mediated transcription of innate immune genes, and this response may be amplified in the presence of certain NF-κB polymorphisms (i.e., NF-κB1). Certain variants of other genes also are associated with alcoholism, including polymorphisms of T NFα, interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), and other components of the IL-1 gene complex, as well as of certain proteins in the space surrounding the cells (i.e., extracellular matrix proteins [ECM]).
Mentions: Stress and AODs, as well as sensory and hormonal signals, activate a regulatory protein (i.e., transcription factor3) called nuclear factor κ–light-chain enhancer of activated B cells (NF-κB) that is produced in large amounts (i.e., is highly expressed) in monocytes and microglia. Although NF-κB is found in most cells, it is the key transcription factor involved in the induction of innate immune genes in microglia and other monocyte-like cells. A wide range of stimuli, such as stress, cytokines, oxidative free radicals, ultraviolet irradiation, bacterial or viral molecules, and many other signaling molecules, increase binding of NF-κB to specific sequences of the DNA. This binding increases the transcription of many genes, particularly those encoding signaling molecules (e.g., chemokines and cytokines) and enzymes (e.g., oxidases and proteases) (figure 3). Studies found that ethanol can increase the binding of NF-κB to its corresponding DNA sequences both in the brains of living organisms (Crews et al. 2006) and in cultured brain slices obtained from a brain area called the hippocampal–entorhinal cortex (HEC) (Zou and Crews 2006). These and other studies also have indicated that ethanol increases transcription of NF-κB target genes, including the genes encoding the following:

Bottom Line: Likewise, altered neuroimmune signaling processes are linked to alcohol-induced negative affect and depression-like behaviors and also regulate alcohol-drinking behavior.Moreover, the expression of several genes and proteins involved in innate immunity is enhanced in addicted people.Finally, specific variants of multiple innate immune genes are associated with the genetic risk for alcoholism in humans, further strengthening the connection between increased brain innate immune gene expression and alcohol addiction.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

ABSTRACT
The neuroimmune system (i.e., the immune system and those components of the nervous system that help regulate immune responses), and in particular the innate immune system, play a role in the development of addictions, including alcoholism, particularly in the context of stressful situations. Certain cells of the neuroimmune system are activated both by stress and by environmental factors such as alcohol, resulting in the induction of genes involved in innate immunity. One of the molecules mediating this gene induction is a regulatory protein called nuclear factor-κB, which activates many innate immune genes. Innate immune gene induction in certain brain regions (e.g., the frontal cortex), in turn, can disrupt decision making, which is a characteristic of addiction to alcohol and other drugs. Likewise, altered neuroimmune signaling processes are linked to alcohol-induced negative affect and depression-like behaviors and also regulate alcohol-drinking behavior. Moreover, the expression of several genes and proteins involved in innate immunity is enhanced in addicted people. Finally, specific variants of multiple innate immune genes are associated with the genetic risk for alcoholism in humans, further strengthening the connection between increased brain innate immune gene expression and alcohol addiction.

No MeSH data available.


Related in: MedlinePlus