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Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267; and the Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
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-1
-stimulated
enterocytes, but the molecular mechanisms are not known. We examined
the role of the transcription factors NF-
B, 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-1 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-1 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-B. 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.
mucosa; inflammation; cytokines; mitogen-activated protein kinase
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