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.