Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis.
Chemokines are involved in the pathogenesis of alcoholic hepatitis and are considered to contribute to the migration of leukocytes into the liver during chronic ethanol intoxication. This work tests the hypothesis that chronic ethanol consumption selectively enhances chemokine release by Kupffer cells and hepatic sinusoidal endothelial cells and migration of inflammatory cells into the liver. Furthermore, enhanced hepatic chemokine secretion may induce an autocrine effect on the ability of Kupffer cells and endothelial cells to chemotax and ingest microbial particles. Male Wistar rats were fed with ethanol in agar block and water for 32 weeks, and were allowed free access to solid food. Results show that after 32 weeks of feeding, leukocyte infiltration and steatosis were observed in the livers of ethanol-fed rats. The majority of the infiltrated cells were CD8+ cells. Serum ALT, endotoxin, MIP-1alpha, MCP-1 and RANTES, (but not CINC and MIP-2) were also increased in the ethanol-fed rats than in the pair-fed group. Isolated Kupffer cells from ethanol-fed rats were primed for enhanced MIP-1alpha, MCP-1, and RANTES production in vitro, while the endothelial cells were primed for enhanced MIP-1alpha release only. Chronic alcohol intoxication was also associated with increased basal H2O2 formation, enhanced nuclear translocation and binding of NF-kappaB, AP-1 and MNP-1 in Kupffer Cells. Chronic ethanol feeding significantly enhanced MNP-1 binding, but not those of NF-kappaB and AP-1 in endothelial cells. Concomitantly, chemokine-induced chemotaxis, E.coli phagocytosis and f-met-leu-phe-induced superoxide anion production by Kupffer cells were downregulated in the ethanol-fed group. Taken together these data demonstrate that prolonged alcohol consumption may compromise the host to hepatitis as a result of increased chemokine production and at the same time may suppress the innate immune function of hepatic non-parenchymal cells.
Bautista
Abraham P
AP
Department of Physiology, NIAAA-Sponsored Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. addressabauti123@cs.com
D000410:Alanine Transaminase / Q000097:blood; D000435:Alcoholic Intoxication / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D019742:Chemokines, CC / Q000096:biosynthesis / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D002908:Chronic Disease; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004926:Escherichia coli; D006519:Hepatitis, Alcoholic / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D019742:Chemokines, CC; C114015:MNP-1 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D013481:Superoxides; D000410:Alanine Transaminase