Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver

Abstract

To understand the mechanisms by which ethanol inhibits hepatocyte proliferation, we studied the effects of ethanol on p42/44 mitogen-activated protein kinase (MAPK), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in normal and regenerating rat liver. Treatment of rat hepatocytes with 100 mM ethanol in vitro for 16 h prolonged the activation of p42/44 MAPK and p38 MAPK induced by various agonists. Such treatment also increased basal JNK activity, but did not potentiate or prolong agonist-induced JNK activation. Ethanol potentiation of the activation of p42/44 MAPK was abolished by pertussis toxin. In contrast, chronic ethanol consumption in vivo inhibited the activation of p42/44 MAPK, p38 MAPK and JNK induced either by partial hepatectomy or by various agonists. However, both acute and chronic ethanol inhibited hepatocyte proliferation induced by insulin and epidermal growth factor. A selective inhibitor of p42/44 MAPK partially prevented the inhibition of hepatocyte proliferation caused by acute, but not by chronic, ethanol exposure, whereas a selective inhibitor of p38 MAPK further inhibited hepatocyte proliferation under both conditions. These data suggest that acute and chronic ethanol inhibit hepatocyte proliferation by different mechanisms. The effect of acute ethanol may be related to the prolongation of p42/44 MAPK activation, whereas inhibition of hepatocyte proliferation by chronic ethanol may be due to inhibition of p38 MAPK activation.

Effect of short-term ethanol on the proliferative response of Swiss 3T3 cells to mitogenic growth factors

“…Exposure to ethanol for 16 h increased the basal JNK activity but there was no change in agonist-induced JNK activation. Whereas chronic ethanol intake for 60 days inhibited the activation of ERK, p38, and JNK induced either by partial hepatectomy or by treatment with various agonists (Zeldin et al, 1996;Chen et al, 1998). In the present study, we observed that acute ethanol treatment for 5-10 min inhibited growth factor-stimulated tyrosine phosphorylation and ERK activation even in the absence of any preincubation with ethanol.…”

“…Acute exposure to ethanol (0-400 mM) for 1 hr had no effect on either basal or serum-and phorbol-12-myristate-13-acetate (PMA)-stimulated ERK activity in a normal mouse embryonic liver cell line, BNLCL2 (Reddy and Shukla, 1996). Exposure to ethanol for 16-24 h prolongs or potentiates the activation of ERK induced by various agonists in a normal mouse embryonic liver cell line (Reddy and Shukla, 1996) and in primary rat hepatocytes (Chen et al, 1998). Exposure to ethanol for 16 h increased the basal JNK activity but there was no change in agonist-induced JNK activation.…”

“…The blockage of growth factor-mediated cell proliferation by ethanol in several systems elicits the hypothesis that growth factor-induced signaling processes are targets of ethanol toxicity. Included are adenylate cyclase (Hoek et al, 1992;Williams and Kelly, 1993), protein kinase C (Pandy, 1996), protein tyrosine kinases (Miyakawa et al, 1997, Resnicoff et al, 1993, Thurston and Shukla, 1992, MAPKs (Roivainen et al, 1995;Reddy and Shukla, 1996;Chen et al, 1998;Tombes et al, 1998;Reddy and Shukla, 2000), phospholipase C and D (Higashi and Hoek, 1991;Hoek et al, 1992;Thurston and Shukla, 1992;Saso et al, 1997;Zhang and Farrell, 1999), transcription factors such as NF-κB (Zeldin et al, 1996) and STAT3 (Chen et al, 1997).…”

Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

“…A similar lack of effect of ethanol was also recently reported in a study in fibroblasts . Ethanol has been shown to inhibit MAPK activation by various stimuli, however, in hepatocellular carcinoma cells (Banerjee et al, 1998), vascular smooth muscle cells (Hendrickson et al, 1998), osteoblasts (Klein et al, 1996), and in vivo in hepatocytes (Chen et al, 1998), rat hippocampus (Davis et al, 1999), and alveolar macrophages (Ouyang et al, 1998). In rat astrocytes, ethanol has been reported to inhibit the PKC-independent acute activation of MAPK by PDGF, but to potentiate the PKC-dependent, sustained activation of MAPK (Luo and Miller 1999a).…”

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

“…This is in line with and extends previous reports on the effect of ethanol on the activation of several protein kinases, such as PKC, JNK, and p42/44 MAPK, that are involved in different signal transduction pathways. 61,62 Because of the complexity of alterations induced by ethanol and DDC intoxication, one must take into account that besides the cytokeratin IFs, a variety of other cellular proteins are affected as well and thus could contribute to the observed cytoskeletal changes.…”