Ethanol and Cytokines in the Central Nervous System.

The innate immune system plays a critical role in the ethanol-induced neuroimmune response in the brain. Ethanol initiates the innate immune response via activation of the innate immune receptors Toll-like receptors (TLRs, e.g., TLR4, TLR3, TLR7) and NOD-like receptors (inflammasome NLRs) leading to a release of a plethora of chemokines and cytokines and development of the innate immune response. Cytokines and chemokines can have pro- or anti-inflammatory properties through which they regulate the immune response. In this chapter, we will focus on key cytokines (e.g., IL-1, IL-6, TNF-α) and chemokines (e.g., MCP-1/CCL2) that mediate the ethanol-induced neuroimmune responses. In this regard, we will use IL-1β, as an example cytokine, to discuss the neuromodulatory properties of cytokines on cellular properties and synaptic transmission. We will discuss their involvement through a set of evidence: (1) changes in gene and protein expression following ethanol exposure, (2) association of gene polymorphisms (humans) and alterations in gene expression (animal models) with increased alcohol intake, and (3) modulation of alcohol-related behaviors by transgenic or pharmacological manipulations of chemokine and cytokine systems. Over the last years, our understanding of the molecular mechanisms mediating cytokine- and chemokine-dependent regulation of immune responses has advanced tremendously, and we review evidence pointing to cytokines and chemokines serving as neuromodulators and regulators of neurotransmission.