Although these interlinked events still need to be substantiate in an animal model of ALD, the emerging picture describes a likely redundant mechanism by which ethanol induction of CYP2E1 and NADPH oxidase systems enhances oxidative stress and sensitizes Kupffer cells to endotoxins, thus promoting inflammation by inhibition of PPARγ function and activation of NF-kB pathways. This line of thought seems to be supported by recent evidences demonstrating that TLR-4 mediates the LPS-induced downregulation of PPARγ by a NF-kB dependent mechanism in macrophages [73]. Loss of PPARγ activity was sufficient to induce a pro-inflammatory state, indicating that PPARγ suppress inflammation under basal conditions by repressing NF-kB activity, while upon activation of TLR4, NF-kB drives down PPARγ expression and thereby obviates any potential anti-inflammatory effects of PPARγ in LPS-stimulated macrophages [73].
