Inhibition of NF-kappa B activation and its target genes by heparin-binding epidermal growth factor-like growth factor.
Many cells upon injury mount extensive, compensatory responses that increase cell survival; however, the intracellular signals that regulate these responses are not completely understood. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been implicated as a cytoprotective agent. We have previously demonstrated that pretreatment of human intestinal epithelial cells with HB-EGF significantly decreased cytokine-induced activation of inducible NO synthase mRNA expression and NO production and protected the cells from apoptosis and necrosis. However, the mechanisms by which HB-EGF exerts these effects are not known. Here we show that cytokine exposure (IL-1beta and IFN-gamma) induced NF-kappaB activation and IL-8 and NO production in DLD-1 cells. Transient expression of a dominant negative form of IkappaBalpha decreased NO production, suggesting that the cytokines stimulated NO production in part through activation of NF-kappaB. HB-EGF dramatically suppressed NF-kappaB activity and IL-8 release and decreased NO production in cells pretreated with HB-EGF. HB-EGF blocked NF-kappaB activation by inhibiting IkappaB kinase activation and IkappaB phosphorylation and degradation, thus interfering with NF-kappaB nuclear translocation, DNA-binding activity, and NF-kappaB-dependent transcriptional activity. The data demonstrate that HB-EGF decreases inflammatory cytokine and NO production by interfering with the NF-kappaB signaling pathway. Inhibition of NF-kappaB may represent one of the mechanisms by which HB-EGF exerts its potent anti-inflammatory and cytoprotective effects.
Mehta
Veela B
VB
Department of Pediatric Surgery, Children's Research Institute, and Ohio State University, Columbus, OH 43205, USA.
Besner
Gail E
GE
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D019073:HT29 Cells; D006493:Heparin / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D004815:Epidermal Growth Factor; D006493:Heparin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human