Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease

Abstract

Kupffer cell-derived cytokines are believed to play pivotal paracrine roles in the pathogenesis of alcoholic liver disease (ALD). To evaluate this hypothesis, Kupffer cell gene expression of tumor necrosis factor-alpha ( m a ) , interleukin (IL)-6, and transforming growth factor-beta 1 (TGFP1) were directly examined in the rat model of ALD. Kupffer cells were isolated from the model after 10 and 17 weeks of intragastric ethanol infusion. These two durations resulted in focal hepatocellular injury and liver fibrogenesis, respectively. Oxidative stress as assessed by the hepatic level of thiobarbituric acid reacting substances, was evident at 10 weeks but more pronounced at 17 weeks. The steady state messenger RNA (mRNA) levels of the cytokines were examined by Northern blot analysis using RNA samples from freshly isolated Kupffer cells, and the release of the cytokines was quantitated ex uiuo using a 3-day culture. The mRNA levels of TNFa and TGFPl were significantly increased by 183% and 204% at 10 weeks and 231% and 295% at 17 weeks in the ethanol-fed rats, respectively. Ex uiuo release of T " activity by control Kupffer cells was undetectable or very low (<2U/105 celldl8 hours) at both time points, but the cells from the ethanol-fed animals secreted appreciably more TNF (27.8 2 7.6 U at 10 weeks and 40.4 2 10.3 U at 17 weeks). The release of the latent TGFPl protein was also coordinately increased by 143% at 10 weeks and 238% at 17 weeks. IL-6 mRNA expression was minimal at 10 weeks, but enhanced most prominently (790%) at 17 weeks, with the ex uiuo release of this cytokine increased 4-fold at the latter time point. These results show coordinate induction of TNFcy, TGFP, and IL-6 expression by Kupffer cells in progression of experimental ALD and support their paracrine roles in the ALD pathogenesis. In particular, the marked induction of Kupffer cell IL-6 gene expres-Abbreviations: ALD, alcoholic liver disease; TNFa, tumor necrosis factoralpha; IL, interleukin; TGF, transforming growth factor; mRNA, messenger RNA.

CYP2E1 and oxidative liver injury by alcohol

“…Rats chronically fed ethanol were more sensitive to the hepatotoxic effects of administration of LPS and had higher plasma levels of TNFα than control rats (196)(197)(198). In the intragastric model of chronic ethanol administration, the development of liver injury coincided with an increase in TNFα, associated with an increase in serum LPS (195,(197)(198)(199). The pioneering studies of Thurman and collaborators showed that anti-TNFα antibody prevented alcohol liver injury in rats (200) and mice lacking the TNFR1 receptor did not develop alcohol liver injury (133).…”

Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines

“…Both proinflammatory and anti-inflammatory as well as growth regulatory properties have been described. 54 Evidence has been presented for an involvement of Kupffer cell-mediated TGF-␤ 1 activation in alcohol-induced liver fibrosis 16 and TGF-␤ 1 expression in liver biopsy specimens from patients with liver disease and in experimental ALD has been reported. 55,17 In the present study TGF-␤ 1 mRNA expression was significantly increased by chronic ethanol treatment, but histologically no signs of changes related to fibrosis could yet be seen.…”

“…[13][14][15] Chronic intragastric ethanol feeding increases the expression of Kupffer cell cytokine messenger RNAs (mRNAs) for TNF-␣, interleukin 6 (IL-6), and transforming growth factor ␤ 1 (TGF-␤ 1 ). 16,17 Peripheral blood monocytes isolated from ALD patients secrete higher levels of TNF-␣ than monocytes from control subjects. 18 In patients with various liver diseases, serum concentrations of proinflammatory cytokines TNF-␣, IL-1, and IL-6 are elevated.…”

Hydrogen peroxide: A link between acetaldehyde-elicited α1(i) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells

“…[10][11][12] A third mechanism by which ethanol induces liver fibrosis is that related to the increased expression of cytokines after liver injury and/or the inflammatory response of the injured tissue. 13,14 Of these, it has been already established that transforming growth factor ␤1 (TGF-␤1) and interleukin 6 are fibrogenic. 15,16 Additional mechanisms could include those related directly or indirectly to the production of adducts between acetaldehyde and/or malondialdehyde and specific proteins.…”