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-kappa B, 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 A(2). NFATc2 is also required for expression of phospholipase D-1 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.