Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-xL proteins

Abstract

Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNFalpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-x(L)) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-x(L) is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-x(L) but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-x(L).

A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury

“…TUNEL staining was significantly increased (P ¼ 0.018) in the livers of the bcl-x þ /-mice, indicating that the damage was due at least in part to apoptosis (Figure 2d) Therefore, Bcl-x L has an important role in protecting the liver from ethanolinduced injury. Additionally, these results strongly suggest that the increase in hepatocellular Bcl-x L expression that occurs in response to chronic ethanol abuse (Hong et al, 2002) affords further protection against injury.…”

“…There is significant evidence that this does indeed occur. For example, hepatic Bcl-x L levels are elevated in alcoholic liver disease (Hong et al, 2002), which is likely to limit hepatocellular injury. However, patients with alcoholic liver disease are at a markedly increased risk for the development of hepatocellular carcinoma (Bergsland, 2001).…”

“…We thought it possible that the tissue level of Bcl-x L is a determinant of the threshold for certain types of injury. We chose to study the role of Bcl-x L in hepatic injury because hepatocellular Bcl-x L expression increases in response to several different hepatic insults: (1) ethanol ingestion increases murine hepatic Bcl-x L expression and Bcl-x L levels are increased in the livers of patients with alcoholic liver disease (Day, 2001;Natori et al, 2001;Ziol et al, 2001;Hong et al, 2002); (2) Bcl-x L expression is upregulated in isolated hepatocytes that are treated with either an anti-Fas antibody or TNF-a (Hatano and Brenner, 2001); (3) Bcl-x L expression is upregulated after partial hepatectomy (Tzung et al, 1997). These findings suggested that changes in Bcl-x L levels within the physiologic range might have a role in determining the extent of hepatocellular injury that occurs in response to hepatic insult.…”

Interplay among cardiotrophin-1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration

“…Despite the fact that IL-6 has demonstrated hepatoprotective properties in various forms of experimental liver damage, 40,41 in NS-398 -treated rats subjected to PH, marked hepatocellular apoptosis and regenerative failure occurs in the presence of IL-6 mRNA hepatic levels approximately 10 times higher than in normal rats after PH. This observation indicates that IL-6 cannot protect liver cells when COX-2 is inhibited and PGs are not normally produced.…”

Physiological potential of cytokines and liver damages

“…IL-6 may protect against hepatocyte apoptosis and participates in mitochondrial DNA repair after alcoholic liver injury. [26] IL-6 may promote human thymus derived monocytes helper 17 (Th17) differentiation and IL-17 production, therefore contributing to ethanol induced liver inflammation. IL-6 is also released along with IL-10, TNF-α and other cytokines by KC after alcohol consumption.…”