The interaction between the brain and the immune system is not unidirectional—that is, immune-system responses also may influence responses in the brain. Recent studies indicate that ethanol causes HMGB1 release in the gut, which activates TLR4. As a result, the gut leaks LPS-like bacterial products, thereby stimulating proinflammatory cytokine induction in the liver, which in turn leads to increased levels of TNF-α and other cytokines in the blood. Qin and Crews (2007, 2012b) discovered that LPS-induced increases in serum TNF-α as well as proinflammatory cytokines led to gene induction in the brain. The proinflammatory cytokines in the blood can be transported across the blood–brain barrier (BBB) by their receptors (e.g., TNFR) (Banks and Erickson 2010; Qin et al. 2007). Using intraperitoneal injections of LPS to stimulate proinflammatory responses in the liver and other tissues and induce proinflammatory cytokines, researchers discovered parallel increases in TNF-α in the blood and brain (Qin et al. 2007). In transgenic mice lacking TNF receptors, however, LPS increased TNF-α only in the blood but not in the brain, suggesting that LPS–TLR4 induction of TNF-α in the
