Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells

Dan D. Hershko, Bruce Robb, Guangju Luo, Per Olof Hasselgren

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Mucosal and enterocyte IL-6 production is increased during sepsis and endotoxemia. Recent studies suggest that cAMP potentiates IL-6 production in endotoxin- or IL-1β-stimulated enterocytes, but the molecular mechanisms are not known. We examined the role of the transcription factors NF-κB, activator protein (AP)-1, CCAAT/enhancer binding protein (C/EBP), and cAMP response element-binding protein (CREB) in cAMP-induced IL-6 production in cultured Caco-2 cells, a human intestinal epithelial cell line. In addition, the role of the protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein (MAP) kinase signaling pathways was examined. Treatment of the cells with IL-1β increased IL-6 production and activated the IL-6 promoter in cells transfected with a luciferase reporter plasmid containing a wild-type IL-6 promoter. These effects of IL-1β were significantly potentiated by cAMP. When the binding sites for the individual transcription factors in the IL-6 promoter were mutated, results indicated that all four transcription factors may be involved in the cAMP-induced activation of the IL-6 gene. Treatment of the Caco-2 cells with cAMP increased the DNA binding activity of CREB, C/EBP, and AP-1, but not NF-κB. By using specific blockers, evidence was found that both PKA and p38 MAP kinase (but not PKC or p42/44 MAP kinase) may be involved in the cAMP-induced potentiation of IL-6 production. The present results suggest that cAMP activates multiple transcription factors involved in the regulation of the IL-6 gene and that the activation of these transcription factors may at least in part explain why cAMP potentiates IL-6 production in stimulated enterocytes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume283
Issue number5 52-5
StatePublished - Nov 1 2002
Externally publishedYes

Fingerprint

Caco-2 Cells
Cultured Cells
Interleukin-6
Transcription Factors
Genes
Enterocytes
Interleukin-1
CCAAT-Enhancer-Binding Proteins
Cyclic AMP Response Element-Binding Protein
Transcription Factor AP-1
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C
Endotoxemia
Mitogen-Activated Protein Kinase 1
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Luciferases
Endotoxins
Transcriptional Activation
Sepsis

Keywords

  • Cytokines
  • Inflammation
  • Mitogen-activated protein kinase
  • Mucosa

ASJC Scopus subject areas

  • Physiology

Cite this

Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells. / Hershko, Dan D.; Robb, Bruce; Luo, Guangju; Hasselgren, Per Olof.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 283, No. 5 52-5, 01.11.2002.

Research output: Contribution to journalArticle

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N2 - Mucosal and enterocyte IL-6 production is increased during sepsis and endotoxemia. Recent studies suggest that cAMP potentiates IL-6 production in endotoxin- or IL-1β-stimulated enterocytes, but the molecular mechanisms are not known. We examined the role of the transcription factors NF-κB, activator protein (AP)-1, CCAAT/enhancer binding protein (C/EBP), and cAMP response element-binding protein (CREB) in cAMP-induced IL-6 production in cultured Caco-2 cells, a human intestinal epithelial cell line. In addition, the role of the protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein (MAP) kinase signaling pathways was examined. Treatment of the cells with IL-1β increased IL-6 production and activated the IL-6 promoter in cells transfected with a luciferase reporter plasmid containing a wild-type IL-6 promoter. These effects of IL-1β were significantly potentiated by cAMP. When the binding sites for the individual transcription factors in the IL-6 promoter were mutated, results indicated that all four transcription factors may be involved in the cAMP-induced activation of the IL-6 gene. Treatment of the Caco-2 cells with cAMP increased the DNA binding activity of CREB, C/EBP, and AP-1, but not NF-κB. By using specific blockers, evidence was found that both PKA and p38 MAP kinase (but not PKC or p42/44 MAP kinase) may be involved in the cAMP-induced potentiation of IL-6 production. The present results suggest that cAMP activates multiple transcription factors involved in the regulation of the IL-6 gene and that the activation of these transcription factors may at least in part explain why cAMP potentiates IL-6 production in stimulated enterocytes.

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