Cytokines are a class of multifunctional proteins that are implicated in cellular communication and activation. Cytokines are critical to the development and functioning of both innate and adaptive immune response, and not just limited to the immune system, but also involved in developmental processes. The cytokines could be of type Th1 (proinflammatory) or Th2 (anti-inflammatory) depending upon their role in the immune system. Cytokines impact tissues in a complex manner that regulates inflammation, cell death, cell proliferation, cell migration, and healing mechanisms. Alcohol is known to alter cytokine levels in a variety of tissues including plasma, lung, liver, brain (Crews et al., 2006a
). These alterations could contribute to changes in the central nervous system leading to long-term changes in behavior and neurodegeneration (). These studies suggest that measurement of cytokines could be a key course of action in understanding alcohol neural pathogenesis. As described below, much of the literature to date has focused on alcohol-induced liver disease (). These studies highlight the importance of examining cytokine changes across the time course of alcoholism to understand the initial changes directly resulting from alcohol use and the secondary pathology that occurs with late stage alcohol-induced tissue damage. The relationship between cytokines and the metabolic consequences of chronic alcoholism has been studied since the early 1990s. Circulating cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 are found to be elevated in both chronic and acute alcohol-induced liver disease. These have been primarily correlated with the metabolic consequences and abnormalities of liver injury due to alcohol intake (Khoruts et al., 1991
). The concentrations of all three cytokines have been correlated with biochemical parameters of liver injury, hepatic protein synthesis and serum IgG concentration.
Summary of potential cytokine changes implicated during human alcoholism
Recently, the measurement of serum TNF-alpha levels has become routine in clinical practice and it has been shown that TNF-alpha contributes to alcohol-induced organ dysfunction, including alcoholic hepatitis. Serum levels of TNF-alpha levels have been demonstrated to be higher in hospitalized alcoholics than in the general population, regardless of alcohol consumption level (Gonzalez-Quintela et al., 2008
). Furthermore the highest TNF-alpha levels, were correlated with liver dysfunction. It is important to note that light-to-moderate drinking had no significant effect on the levels of serum TNF-alpha levels (Gonzalez-Quintela et al., 2008
In a recent study, alcoholic patients were examined for the production of cytokines by peripheral blood (PB) monocytes and this was related to the amount of alcohol intake, as well as liver disease (Laso et al., 2007
). As shown in , a significant increase in spontaneous production of IL1-beta, IL6, IL12, and TNF-alpha was observed in chronic alcoholics without liver disease compared with those who are alcoholic with liver cirrhosis. On the other hand, chronic alcoholics with liver disease still consuming alcohol showed abnormally low production of IL1-beta and TNF-alpha (Laso et al., 2007
In addition to liver injury, there is a growing understanding of the role of cytokines in alcohol-induced neurodegeneration. In a rat model, alcohol-induced neurodegeneration is shown to be due to neuronal death during intoxication and is related to increased oxidative stress and proinflammatory proteins that are neurotoxic (Crews and Nixon, 2009
). Degeneration is associated with increased NF-kappaB proinflammatory transcription and decreased CREB transcription. However, abstinence after binge ethanol intoxication results in neurogenesis and regeneration of brain structure and function (Crews and Nixon, 2009
). Studies using animal models have documented the effects of alcohol on acute adolescent neurogenesis by alcohol (Crews et al., 2006b
). Studies on human postmortem brains from alcoholics have shown increased concentrations of monocyte chemoattractant protein 1 (MCP-1) and microglial activities that may have contributed to the alcohol-induced pathogenesis (He and Crews, 2008
The interactions between altered levels of cytokines in alcoholics and infectious agents provide mechanistic insight into alcohol pathobiology. (Molina et al., 2006
)have studied the effect of chronic alcoholism on nutritional, metabolic and immune alterations during the initial 10-month asymptomatic phase of SIV infection in nonhuman primate rhesus macaques. Chronic alcohol/SIV(+) animals showed a higher viral load at 3 months post-SIV infection, as well as muscle TNF-alpha mRNA expression was markedly increased (Molina et al., 2006
Interestingly, there are also reported associations between cytokine gene polymorphisms and predisposition to alcoholism. Marcos and colleagues reported that an IL-10 gene polymorphism is associated with alcoholism and not with alcoholic liver disease as a result of alcoholism (Marcos et al., 2008
). This study in Spanish subjects demonstrated that the frequency of allele A carriers (CA and AA genotypes) was significantly higher in patients with alcohol dependence and alcohol abuse than in healthy controls. The mechanism by which cytokine polymorphisms such as these contribute to alcoholic predisposition remain to be understood but further emphasize the importance of examining cytokine functions in alcohol abuse and alcoholism.
These examples from the alcohol research field are exciting first steps in understanding the relationship of alcohol intake and alcohol-induced tissue damage to levels of circulating cytokines. Much more detailed analysis of many more cytokines is needed to understand the global pattern of cytokine levels in the plasma. While the focus of this review is on the use of cytokines in diagnostic biomarkers, these findings will also add mechanistic insight into the effects of alcohol on a variety of organ systems.
With the promise of cytokines as diagnostic markers there is also the potential that cytokines alone will not provide a sufficiently sensitive and specific test. Addition of other circulating proteins, such as growth factors, to a biomarker panel may reach the required accuracy. Interactions of alcohol with levels of growth factor during pregnancy highlight the potential roles of circulating factors in neurodevelopment. Studies have examined peripheral hepatocyte growth factor (HGF), epidermal growth factor (EGF) and placenta growth factor (PlGF) in pregnant women consuming alcohol (Vuorela et al., 2002
). The data indicate that alcohol abuse during pregnancy has a profound effect on circulating EGF and PlGF but not HGF concentrations. However, the data showed no associations between clinical outcome such as birth weight, Apgar score and placental weight and maternal circulating cytokines analyzed during pregnancy. Interestingly, although there were clear differences in the cytokine concentrations between alcohol abusing and alcohol abstinent women, the changes were speculated to be due to altered expression, tissue release or breakdown of these cytokines and thus could not be correlated. Thus, the changes occurring during pregnancy could be primarily due to alcohol or could be part of a cascade of secondary events leading to alcohol-induced placental pathophysiology (Vuorela et al., 2002