Direct hepatotoxic effect of KC chemokine in the liver without infiltration of neutrophils.
KC is a mouse homolog of human chemokine gro-alpha (CXCL1), expression of which is increased in liver diseases. We show that activated, but not quiescent, hepatic stellate cells (HSCs) express KC. Hepatic stellate cells constitutively express the KC receptor, CXCR2. Addition of recombinant KC to HSCs undergoing activation in culture increases secretion and processing of Type I collagen. Overexpression of endogenous KC in the mouse liver could be achieved by an intraperitoneal injection of CCl(4), followed after 24 hrs by an injection of recombinant KC into circulation. This protocol resulted in about a 14-fold increase in concentration of KC protein in the liver. Overexpression of KC was associated with upregulation of the mRNA for CXCR2 and MIP-2 and with necrosis and increased synthesis of Type I collagen. This suggests that KC has a direct hepatotoxic effect, which led to a massive liver necrosis after 48 hrs. No accumulation of neutrophils was seen in the livers as judged by histology and reverse transcriptase-polymerase chain reaction analysis of myeloperoxidase mRNA. Autostimulation of KC and CXCR2 expression by recombinant KC protein in the mice with preexisting liver injury indicates a positive feedback regulation. Such regulation and direct hepatotoxicity of KC with increased collagen synthesis represent novel findings about the role of KC/ gro-alpha in liver pathology.
Stefanovic
Lela
L
Department of Biomedical Science, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Brenner
David A
DA
Stefanovic
Branko
B
D000818:Animals; D002252:Carbon Tetrachloride Poisoning; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000235:genetics* / Q000633:toxicity*; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011691:Puromycin; D003513:Cycloheximide