Protective function of complement against alcohol-induced rat liver damage.
The complement system can promote tissue damage or play a homeostatic role in the clearance and disposal of damaged tissue. We assessed the role of the terminal complement pathway in alcohol-induced liver damage in complement C6 (C6-/-) genetically deficient rats. C6-/- and corresponding C6+/+ rats were continuously exposed to ethanol by feeding ethanol-supplemented liquid diet for six weeks. Liver samples were analyzed for histopathology and complement component deposition by immunofluorescence microscopy. Prostaglandin E receptors and cytokine mRNA levels were analyzed by RT-PCR and plasma cytokines by ELISA. Deposition of complement components C1, C3, C8 and C9 was observed in C6+/+ rats, but not in C6-/- animals. The histopathological changes, the liver weight increase and the elevation of the plasma pro-/anti-inflammatory TNF-alpha/IL-10 ratio were, on the other hand, more marked in C6-/- rats. Furthermore, ethanol enhanced the hepatic mRNA expression of the prostaglandin E receptors EP2R and EP4R exclusively in the C6-/- rats. Our results indicate that a deficient terminal complement pathway predisposes to tissue injury and promotes a pro-inflammatory cytokine response. This suggests that an intact complement system has a protective function in the development of alcoholic liver damage.
Bykov
Igor L
IL
Alcohol Research Center, National Public Health Institute, POB 33, 00251 Helsinki, Finland.
Väkevä
Antti
A
Järveläinen
Harri A
HA
Meri
Seppo
S
Lindros
Kai O
KO
D000437:Alcoholism / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003183:Complement C6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003183:Complement C6; D016207:Cytokines; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D003165:Complement System Proteins