Cytochrome P4502E1 primes macrophages to increase TNF-α production in response to lipopolysaccharide

Abstract

Cao, Qi, Ki M. Mak, and Charles S. Lieber. Cytochrome P4502E1 primes macrophages to increase TNF-␣ production in response to lipopolysaccharide.

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…These results may indicate that CYP2E1 is not as important as NADPH oxidase. However, the expression of CYP2E1 may have a permissive role for priming the macrophages for their sensitization with elevated NADPH oxidase, hydrogen peroxide, NF-κB, and TNFα levels following exposure to LPS (Cao et al, 2005). Suppression of CYP2E1 with an inhibitor diallyl sulfide or NADPH oxidase by its inhibitor diphenyleneiodonium equally decreased the levels of hydrogen peroxide, suggesting both enzymes are involved in producing oxidative stress in this model.…”

“…However, alcohol-or fructose-associated gut leakage and endotoxin can stimulate hepatic Kupffer cells with infiltration of neutrophils and monocytes into the liver. Activation of Kupffer cells and infiltrated immune cells can increase nitroxidative stress, HIF, and NF-κB, which produces cytokines, chemokines, and iNOS Yun et al, 2014), where CYP2E1 is directly involved or at least plays a permissive role in activating immune cells (Barnes, Roychowdhury, & Nagy, 2014;Cao, Mak, & Lieber, 2005;Lieber, 1997). In addition, activated immune cells can stimulate membrane association of the subunits of NADPH oxidase, producing ROS (Kim, Nagy, & Park, 2014).…”

Ubiquitin-Conjugating Enzyme 9 Phosphorylation as a Novel Mechanism for Potentiation of the Inflammatory Response

“…LPS levels are high in the blood of alcoholics and in ethanol-fed rodents. 1 Kupffer cells become activated in response to elevated levels of LPS during ethanol feeding 2 and produce immunoregulatory cytokines, such as tumor necrosis factor a (TNF-a), IL-1b, IL-6, arachidonic acid, as well as reactive oxygen species. 3 The NF-kB proteins play a major role in LPS-mediated inflammatory response by activating the expression of the above cytokine genes.…”

Oxidative Stress and Ethanol Toxicity

“…It is therefore proposed that this enzyme may contribute to oxidative stress caused by alcohol. This isozyme has also been shown to be induced in macrophages; macrophages overexpressing CYP2E1 have a more robust response to stimulation in culture [ 18 ], which may contribute to the 'priming' effect of alcohol on these cells (see Sect. 11.3.2 ).…”