HIF-1alpha expression in response to lipopolysaccaride mediates induction of hepatic inflammatory cytokine TNFalpha.
HIF-1alpha is a transcription factor that acts as a master regulator of gene expression induced by hypoxia. Recent studies have demonstrated that the potent inflammatory factor, lipopolysaccharide (LPS), can also activate HIF-1alpha in myeloid cells. However, the molecular mechanisms at the transcriptional level of HIF-1alpha induction by LPS remained undefined. Here, we investigated the regulatory mechanism of HIF-1alpha expression by LPS in hepatocytes and identified that LPS-induced HIF-1alpha mediate gene transcription of a typical inflammatory mediator, tumor-necrosis factor alpha (TNFalpha). Increased HIF-1alpha gene expression by LPS was defined in a series of hepatic cell lines by RT-PCR, Western blotting and promoter transactivation assay. The JNK signaling and c-Jun activation were required to induce the HIF-1alpha gene transcription by LPS. The finding that a cascade transcriptional activation of distinct set of transcription factors, c-Jun and HIF-1alpha, in response to LPS stimulation associates with induction of TNFalpha gene transcription lends new insights into the functional mechanisms by which complex patterns of gene regulation on LPS-derived HIF activation are achieved.
Kim
Hye Young
HY
Department of Molecular Biology, Pusan National University, Busan 609-735, Republic Korea.
Kim
Young Hee
YH
Nam
Bo-Hye
BH
Kong
Hee Jeong
HJ
Kim
Hyung Hoi
HH
Kim
Yoon Jin
YJ
An
Won Gun
WG
Cheong
Jaehun
J
D001424:Bacterial Infections / Q000378:metabolism / Q000503:physiopathology; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases