Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor α, reduced glutathione, and transforming growth factor β–dependent mechanisms
✍ Scribed by Francisco Javier Cubero; Natalia Nieto
- Book ID
- 102850233
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 929 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Because of the contribution of ethanol and polyunsaturated fatty acids (PUFAs) to alcoholic liver disease, we investigated whether chronic ethanol administration and arachidonic acid (AA) could synergistically mediate Kupffer cell (KC) activation and modulate the stellate cell (HSC) fibrogenic response. Results: (1) the effects of ethanol and AA on KC and HSC were as follows: Cell proliferation, lipid peroxidation, H 2 O 2 , O 2 ⅐ ؊ , nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activity, and tumor necrosis factor alpha (TNF-␣) were higher in KC ethanol than in KC control , and were enhanced by AA; HSC ethanol proliferated faster, increased collagen, and showed higher GSH than HSC control , with modest effects by AA. (2) AA effects on the control co-culture: We previously reported the ability of KC to induce a pro-fibrogenic response in HSC via reactive oxygen species (ROS)-dependent mechanisms; we now show that AA further increases cell proliferation and collagen in the control co-culture. The latter was prevented by vitamin E (an antioxidant) and by diphenyleneiodonium (a NADPH oxidase inhibitor). (3) Ethanol effects on the co-cultures: Co-culture with KC control or KC ethanol induced HSC control and HSC ethanol proliferation; however, the pro-fibrogenic response in HSC ethanol was suppressed because of upregulation of TNF-␣ and GSH, which was prevented by a TNF-␣ neutralizing antibody (Ab) and by L-buthionine-sulfoximine, a GSH-depleting agent. (4) Ethanol plus AA effects on the co-cultures: AA lowered TNF-␣ in the HSC control co-cultures, allowing for enhanced collagen deposition; furthermore, AA restored the pro-fibrogenic response in the HSC ethanol co-cultures by counteracting the up-regulation of TNF-␣ and GSH with a significant increase in GSSG and in pro-fibrogenic transforming growth factor beta (TGF-). Conclusion: These results unveil synergism between ethanol and AA to the mechanism whereby KC mediate ECM remodeling and suggest that even if chronic ethanol consumption sensitizes HSC to up-regulate anti-fibrogenic signals, their effects are blunted by a second "hit" such as AA.