Proliferative effects of CXC chemokines in rat hepatocytes in vitro and in vivo.
The CXC chemokines have well-documented neutrophil chemotactic, angiogenic, and mitogenic properties. The current investigations evaluate the effects of interleukin-8 (IL-8), epithelial neutrophil activating protein (ENA-78), and macrophage inflammatory peptide-2 (MIP-2) on hepatocyte proliferation in vitro and liver regeneration in vivo. Primary rat hepatocytes were isolated by collagenase digestion and exposed to incremental doses of IL-8, ENA-78, or MIP-2, and cellular proliferation was measured via tritiated thymidine incorporation. These experiments demonstrated significant increases in hepatocyte proliferation in response to IL-8, ENA-78, and MIP-2. Next, rats were sacrificed in a time-dependent manner following 70% hepatectomy or sham laparotomy, and hepatic tissue levels of MIP-2 and ENA-78 were measured using an ELISA. ENA-78 and MIP-2 were significantly elevated following 70% hepatectomy as compared with sham-operated control animals. Rats undergoing 70% hepatectomy were then treated with neutralizing anti-ENA-78 serum, anti-MIP-2 serum, or preimmune control serum, and liver regeneration was evaluated. These experiments demonstrated that neutralization of ENA-78 or MIP-2 slowed the rate of liver regeneration. These data suggest that the CXC chemokines may be important agents for the induction of hepatocyte proliferation and may be important molecules in vivo in the setting of liver injury, repair, and regeneration.
Colletti
L M
LM
Department of Surgery, University of Michigan Medical School, Ann Arbor 48109, USA. colletti@umich.edu
Green
M
M
Burdick
M D
MD
Kunkel
S L
SL
Strieter
R M
RM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000494:pharmacology; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D015846:Monokines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000906:Antibodies; C486263:CXCL5 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008934:Mitogens; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor