Role of interleukin-6 in the control of DNA synthesis of hepatocytes: involvement of PKC, p44/42 MAPKs, and PPARdelta.
Interleukin-6 (IL-6) is a pleiotropic cytokine with a pivotal role in normal hepatic growth and liver regeneration. Therefore, in the present study, we examined the effect of IL-6 on cell proliferation and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased the level of [(3)H]thymidine incorporation in a time (>or= 6 hr)- and a dose (>or= 0.1 ng/ml)-dependent manner. Indeed, IL-6 increased the number of BrdU-positive cells and the total number of cells. IL-6 (10 ng/ml) increased the level of IL-6Ralpha and glycoprotein (gp) 130 (IL-6Rbeta) protein expression, Janus Kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, PKC, p44/42 MAPKs phosphorylation, and PPARdelta protein expression. Inhibition of each pathways blocked IL-6-induced [(3)H]thymidine incorporation increase. IL-6 increased c-fos, c-jun, and c-myc proto-oncogene mRNA levels and the percentage of cells in the S phase according to fluorescence-activated cell sorter (FACS) analysis. IL-6-induced G1/S phase progression was inhibited by AG 490 (2x10(-5) M, JAK2 inhibitor), a STAT3 inhibitor peptide (10(-5) M), bisindolylmaleimide I (10(-6) M, PKC inhibitor), PD 98059 (10(-5) M, p44/42 MAPKs blocker), or PPARdelta-specific small interfering RNAs (siRNAs). In conclusion, IL-6 stimulates the proliferation of primary cultured chicken hepatocytes through PKC, p44/42 MAPKs, and PPARdelta pathways.
Suh
Han Na
HN
Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
Lee
Sang Hun
SH
Lee
Min Young
MY
Lee
Yu Jin
YJ
Lee
Jang Hern
JH
Han
Ho Jae
HJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004247:DNA / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D015850:Interleukin-6 / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D047494:PPAR delta / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D015850:Interleukin-6; C000715470:MAS1 protein, human; D047494:PPAR delta; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019947:Receptors, Interleukin-6; D050791:STAT Transcription Factors; D004247:DNA; D053612:Janus Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3