Role of the CCAAT/Enhancer-binding Protein NFATc2 Transcription Factor Cascade in the Induction of Secretory Phospholipase A2

Teddy T.C Yang,Peter M.U Ung,Mercedes Rincón,Chi-Wing Chow

doi:10.1074/jbc.m511214200

Abstract

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.

Highlights

From the ‡Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461 and the §Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont 05401
Role of NFAT in the Inflammatory Response in Nonimmune Cells—In this study, we have demonstrated that inflammatory cytokines induce NFATc2 expression in hepatocytes
These results provide a mechanism for NFATc2 expression and expand the repertoire of NFAT function to the acute-phase response in the liver

Summary

Introduction

From the ‡Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461 and the §Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont 05401 Inflammatory cytokines such as interleukin-1 and tumor necrosis factor-␣ modulate a transcription factor cascade in the liver to induce and sustain an acute and systemic defense against foreign entities. Upon stimulation with inflammatory cytokines, the expression of plasma proteins, proteases, and procoagulants in hepatocytes is increased in part by pre-existing and newly synthesized transcription factors [4, 5] Proteins involved in this transcription factor cascade include NF-␬B, STAT (signal transducer and activator of transcription), and CCAAT/ enhancer-binding protein (C/EBP) family members. Understanding the basic mechanism of activation of the transcription factor cascade mediated by inflammatory cytokines will shed new light on the treatment of chronic inflammation such as sepsis and atherosclerosis

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