Role of the CCAAT/enhancer-binding protein NFATc2 transcription factor cascade in the induction of secretory phospholipase A2.
Inflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha modulate a transcription factor cascade in the liver to induce and sustain an acute and systemic defense against foreign entities. The transcription factors involved include NF-kappaB, STAT, and CCAAT/enhancer-binding protein (C/EBP). Whether the NFAT group of transcription factors (which was first characterized as playing an important role in cytokine gene expression in the adaptive response in immune cells) participates in the acute-phase response in hepatocytes is not known. Here, we have investigated whether NFAT is part of the transcription factor cascade in hepatocytes during inflammatory stress. We report that interleukin-1 or tumor necrosis factor-alpha increases expression of and activates NFATc2. C/EBP-mediated NFATc2 induction is temporally required for expression of type IIA secretory phospholipase A2. NFATc2 is also required for expression of phospholipase D1 and the calcium-binding protein S100A3. Thus, a C/EBP-NFATc2 transcription factor cascade provides an additional means to modulate the acute-phase response upon stimulation with inflammatory cytokines.
Yang
Teddy T C
TT
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ung
Peter M U
PM
Rincón
Mercedes
M
Chow
Chi-Wing
CW
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D054501:Group II Phospholipases A2; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011401:Promoter Regions, Genetic; D009418:S100 Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D007375:Interleukin-1; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D009418:S100 Proteins; C082356:S100A3 protein, human; C489950:S100a3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D010739:Phospholipase D; C106801:phospholipase D1