Role of Myeloid Cell-Specific Adenylyl Cyclase Type 7 in Lipopolysaccharide- and Alcohol-Induced Immune Responses

Clinical and experimental evidence indicates that alcohol use causes various abnormalities in the immune system and compromises immune functions. However, the mechanistic understanding of ethanol's effects on the immune system remains limited. Cyclic AMP (cAMP) regulates multiple processes, including immune responses. Earlier research indicated that type 7 adenylyl cyclase (AC7) regulates the immune system and is highly responsive to ethanol. Therefore, we hypothesized that AC7 is a central player in regulating the effects of alcohol on innate immune responses. To test this hypothesis, we utilized a myeloid lineage-specific AC7 KO mouse model and compared the effects of acute and chronic ethanol treatment on their innate immune responses induced by systemic lipopolysaccharide (LPS) challenge. Our results demonstrate that AC7 KO mice had significantly lower survival rates under LPS challenge. Chronic ethanol consumption rescued AC7 KO mice from LPS-induced death. AC7 KO and ethanol, acute and chronic, affected several measurements of cytokine mRNA expressions, including IL-1β, TNFα, IL-6, and IL-10 in the lung and liver. In a few cases, statistical analysis indicated that these two factors interacted, suggesting that AC7 played some role in ethanol's effect on cytokine expression. Thus, this study demonstrated AC7's role in ethanol's effect on the innate immune response.