Excessive ethanol (EtOH) consumption impairs immune function, evident in the increased incidence and severity of certain cancers and viral infections seen in alcoholic patients;however its mechanistic role in immunosuppression is poorly understood. Because natural killer (NK) cells play a vital role in tumor surveillance and in defense against virus infections, the overall objective of this proposal is to identify the underlying in vivo mechanisms by which chronic EtOH inhibits NK cell responses. This will be accomplished under conditions of murine cytomegalovirus (MCMV) infection;a well-established model system used to study NK cell function. NK cells are quickly activated by cytokines induced in response to MCMV infection. Importantly, there is evidence that cytokine production is profoundly altered by exposure to EtOH. With this in mind, the central hypothesis of the proposed research is that chronic ethanol consumption modulates the cytokine balance that contributes to the regulation of NK cell responses. This hypothesis is based on the following observations. First, EtOH inhibits cytokines that modulate two NK cell effector functions used in defense against viral pathogens and tumors: cytotoxicity (killing) and cytokine production. Specifically, EtOH inhibits polyinosinic-polycytidylic acid (poly-I:C)-induced NK cell cytotoxicity. Poly-I:C is a chemical inducer of type 1 interferons (IFN-1/2), which activate NK cell cytotolytic effectors during MCMV infection. Second, EtOH exposure affects the release of interleukin-12, a cytokine that supports NK cell production of the regulatory cytokine IFN-3 and cytotoxicity. Third, dendritic cells, which are important sources of IFN-1/2 and IL-12, are sensitive to EtOH exposure. Based on these observations, we propose to address how EtOH-altered cytokine function impact NK cell responses to MCMV infection. It is hypothesized that chronic EtOH intake suppresses production of IFN-1/2 and IL-12 from pDC subsets, and such suppression results from modulations in the intracellular signaling pathways involved in pDC activation.
In Aim 1, we will test the hypothesis by evaluating the effects of chronic EtOH on cytokine production, the expression of intermediate mediators in the TLR7/9- MyD88 signaling pathway, and the functional response of the downstream transcription factors IRF-7 and NFkB in pDC subsets. Increasing evidence supports the idea that pDC-derived cytokines are essential in initiating NK cell responses. Therefore, it is hypothesized that the suppressive effects of chronic EtOH on NK cell responses result from impaired production of cytokines in pDC subsets.
In Aim 2, we will test the hypothesis by evaluating the effects of chronic EtOH on NK cell trafficking and delivery of effector function, and on pDC and NK cell interactions. The studies will elucidate novel information on the molecular mechanisms underlying cytokine dysregulation associated with chronic alcohol abuse. Identification of such mechanisms should prove valuable in understanding suppression of immune responses associated with NK cells and may have important translational implications for the development of potential therapeutics for alcoholic patients.
There is substantial evidence that alcohol consumption increases the risk of developing cancers of various organs. Excessive alcohol consumption also impairs immune function, evident in the increased frequency and severity of infections seen in alcoholic patients. Because NK cells promote tumor surveillance and can inhibit the growth and spread of certain cancers, understanding the mechanisms that promote inhibition of NK cell activity under conditions of alcohol exposure will have significant implications regarding efficacies of anticancer treatment protocols, and will address a research objective of this announcement.
| Crane, Meredith J; Gaddi, Pamela J; Salazar-Mather, Thais P (2012) UNC93B1 mediates innate inflammation and antiviral defense in the liver during acute murine cytomegalovirus infection. PLoS One 7:e39161 |
| Gaddi, Pamela J; Crane, Meredith J; Kamanaka, Masahito et al. (2012) IL-10 mediated regulation of liver inflammation during acute murine cytomegalovirus infection. PLoS One 7:e42850 |
