The JAK-STAT (Janus Kinase - Signal Transducer and Activator of Transcription) signaling pathway activated by more than 35 different cytokines or growth factors has been implicated in a variety of cellular functions in the hematopoietic, immune, neuronal and hepatic systems. Ethanol inhibition of JAK-STAT activation may be a mechanism by which ethanol causes a wide variety of disorders in many organs. Acute exposure of rat hepatocytes to 25-100 mM ethanol significantly inhibits interleukin 6-, interferon gamma- or growth hormone-induced STAT activation. Chronic ethanol consumption significantly attenuates hepatic STAT3 activation induced by partial hepatectomy or interleukin 6. Acute ethanol (25-100 mM) exposure also significantly attenuates thrombopoietin- or interleukin 6-induced STAT activation in hematopoietic cells (BAF3/mp1 cells, platelets, U937, and AF10 cells), and ciliary neurotrophic factor-induced STAT activation in neuronal cells (NBTF neuroblastoma). The target sites of ethanol in the JAK-STAT signaling pathway will be explored by analyzing the effects of ethanol on cytokine-induced STAT phosphorylation, dimerization, translocation, JAK phosphorylation, receptor phosphorylation and ligand-receptor binding. The effects of chronic ethanol on the JAK-STAT pathway will be explored by examining JAK-STAT activation in vivo in rats fed with an ethanol containing diet. Identification of ethanol inhibition of the JAK-STAT signaling pathway in various tissues will enhance our understanding of the pathogenesis and progression of a wide variety of disorders caused by ethanol, such as antiregenerative effects, thrombocytopenia and fetal alcohol syndrome, and may also prove helpful in the design of novel drugs with therapeutic potential in alcohol-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012637-02
Application #
6371632
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
2000-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$175,182
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Hong, Feng; Kim, Won-Ho; Tian, Zhigang et al. (2002) 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-x(L) proteins. Oncogene 21:32-43
Guo, Tai L; Zhang, Ling X; Chen, Jian P et al. (2002) Differential STAT5 activation and phenotypic marker expression by immune cells following low levels of ethanol consumption in mice. Immunopharmacol Immunotoxicol 24:121-38
Gao, B; Shen, X; Kunos, G et al. (2001) Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. FEBS Lett 488:179-84
Chen, J; Clemens, D L; Cederbaum, A I et al. (2001) Ethanol inhibits the JAK-STAT signaling pathway in freshly isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism. Clin Biochem 34:203-9
Nguyen, V A; Chen, J; Hong, F et al. (2000) Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent Biochem J 349:427-34
Tian, Z; Shen, X; Feng, H et al. (2000) IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway. J Immunol 165:3959-65
Liu, J; Shen, X; Nguyen, V A et al. (2000) Alpha(1) adrenergic agonist induction of p21(waf1/cip1) mRNA stability in transfected HepG2 cells correlates with the increased binding of an AU-rich element binding factor. J Biol Chem 275:11846-51
Shen, X; Tian, Z; Holtzman, M J et al. (2000) Cross-talk between interleukin 1beta (IL-1beta) and IL-6 signalling pathways: IL-1beta selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (STAT1) by a proteasome-dependent mechanism. Biochem J 352 Pt 3:913-9
Shen, X; Hong, F; Nguyen, V A et al. (2000) IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3. FEBS Lett 480:132-6
Spector, M; Nguyen, V A; Sheng, X et al. (2000) Activation of mitogen-activated protein kinases is required for alpha1-adrenergic agonist-induced cell scattering in transfected HepG2 cells. Exp Cell Res 258:109-20