Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB.
Human esophageal epithelial cells play a key role in esophageal inflammation in response to acidic pH during gastroesophageal reflux disease (GERD), increasing secretion of IL-6 and IL-8. The mechanisms underlying IL-6 and IL-8 expression and secretion in esophageal epithelial cells after acid stimulation are not well characterized. We investigated the role of PKC, MAPK, and NF-kappaB signaling pathways and transcriptional regulation of IL-6 and IL-8 expression in HET-1A cells exposed to acid. Exposure of HET-1A cells to pH 4.5 induced NF-kappaB activity and enhanced IL-6 and IL-8 secretion and mRNA and protein expression. Acid stimulation of HET-1A cells also resulted in activation of MAPKs and PKC (alpha and epsilon). Curcumin, as well as inhibitors of NF-kappaB (SN-50), PKC (chelerythrine), and p44/42 MAPK (PD-098059) abolished the acid-induced expression of IL-6 and IL-8. The JNK inhibitor SP-600125 blocked expression/secretion of IL-6 but only partially attenuated IL-8 expression. The p38 MAPK inhibitor SB-203580 did not inhibit IL-6 expression but exerted a stronger inhibitory effect on IL-8 expression. Together, these data demonstrate that 1) acid is a potent inducer of IL-6 and IL-8 production in HET-1A cells; 2) MAPK and PKC signaling play a key regulatory role in acid-mediated IL-6 and IL-8 expression via NF-kappaB activation; and 3) the anti-inflammatory plant compound curcumin inhibits esophageal activation in response to acid. Thus IL-6 and IL-8 expression by acid may contribute to the pathobiology of mucosal injury in GERD, and inhibition of the NF-kappaB/proinflammatory cytokine pathways may emerge as important therapeutic targets for treatment of esophageal inflammation.
Rafiee
Parvaneh
P
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. prafiee@mcw.edu
Nelson
Victoria M
VM
Manley
Sharon
S
Wellner
Michael
M
Floer
Martin
M
Binion
David G
DG
Shaker
Reza
R
D000873:Anthracenes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000494:pharmacology; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D004947:Esophagus / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009092:Mucous Membrane / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
D000873:Anthracenes; D000893:Anti-Inflammatory Agents; D053119:Benzophenanthridines; C508606:CXCL8 protein, human; D005419:Flavonoids; C508600:IL6 protein, human; D007093:Imidazoles; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C118258:SN50 peptide; C432165:pyrazolanthrone; C016299:chelerythrine; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase; D003474:Curcumin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one