Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-(kappa)B and STAT3.
A novel protein, proteolysis-inducing factor (PIF), has been isolated from the urine of patients with pancreatic cancer and is capable of inducing muscle proteolysis in vitro. Only adult skeletal muscle and liver exhibit substantial binding of PIF. We have investigated the effect of PIF on hepatic gene expression. Primary cultures of human hepatocytes and the human cell line HepG2 were incubated in the presence of PIF to assess its effects on hepatic transcription factors, proinflammatory cytokine production, and acute phase proteins. PIF activates both the transcription factors NF-kB and STAT3, which result in the increased production of IL-8, IL-6, and C-reactive protein and the decreased production of transferrin. The function of PIF, beyond muscle degradation, is unknown but here we show that it is involved in hepatic gene expression, and is thus likely to be involved in the proinflammatory response observed in cachexia. These results may also suggest a potential role for PIF during embryonic development. The expression of PIF peaks during the embryonic period E8 to E9, a stage that is crucial in the development of skeletal muscle and liver and during which both NF-kB and STAT3 activation can also be observed.
Molecular Immunology Group, Department of Clinical and Surgical Sciences, Edinburgh University, U.K. twatchorn@ed.ac.uk
T M
TM
Watchorn
I
I
Waddell
N
N
Dowidar
J A
JA
Ross
D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology*; D002100:Cachexia / Q000503:physiopathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001798:Blood Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C042057:proteolysis-inducing peptide; D018799:Intercellular Adhesion Molecule-1