Faculty Collaboration Database

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. Am J Physiol Gastrointest Liver Physiol 2009 Feb;296(2):G388-98

Date

12/17/2008

Pubmed ID

19074641

DOI

10.1152/ajpgi.90428.2008

Scopus ID

2-s2.0-59449103458 (requires institutional sign-in at Scopus site)   89 Citations

Abstract

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.

Author List

Rafiee P, Nelson VM, Manley S, Wellner M, Floer M, Binion DG, Shaker R

Author

Reza Shaker MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anthracenes
Anti-Inflammatory Agents
Benzophenanthridines
Cell Line
Curcumin
Enzyme Activation
Epithelial Cells
Esophagus
Flavonoids
Humans
Hydrogen-Ion Concentration
Imidazoles
Interleukin-6
Interleukin-8
Mitogen-Activated Protein Kinases
Mucous Membrane
NF-kappa B
Peptides
Protein Kinase C
Protein Kinase Inhibitors
Pyridines
Signal Transduction
Telomerase
Time Factors
Transcription, Genetic
Up-Regulation