Parthenolide inhibits ERK and AP-1 which are dysregulated and contribute to excessive IL-8 expression and secretion in cystic fibrosis cellsReportar como inadecuado

Parthenolide inhibits ERK and AP-1 which are dysregulated and contribute to excessive IL-8 expression and secretion in cystic fibrosis cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Inflammation

, 8:26

First Online: 12 October 2011Received: 13 October 2010Accepted: 12 October 2011


BackgroundExcessive secretion of IL-8 characterizes cystic fibrosis CF. This has been attributed to excessive activation of epithelial cell I-κB Kinase and-or NFκB. Maximum IL-8 production requires 3 cooperative mechanisms: 1 release of the promoter from repression; 2 activation of transcription by NFκB and AP-1; 3 stabilization of mRNA by p38-MAPK. Little is known about regulation of IL-8 by MAPKs or AP-1 in CF.

MethodsWe studied our hypothesis in vitro using 3-cellular models. Two of these models are transformed cell lines with defective versus normal cystic fibrosis transmembrane conductance regulator CFTR expression: an antisense-sense transfected cell line and the patient derived IB3-1-S9. In the third series of studies, we studied primary necropsy human tracheal epithelial cells treated with an inhibitor of CFTR function. All cell lines were pretreated with parthenolide and then stimulated with TNFα and-or IL-1β.

ResultsIn response to stimulation with TNFα and-or IL-1β, IL-8 production and mRNA expression was greater in CF-type cells than in non-CF controls. This was associated with enhanced phosphorylation of p38, ERK1-2 and JNK and increased activation of AP-1. Since we previously showed that parthenolide inhibits excessive IL-8 production by CF cells, we evaluated its effects on MAPK and AP-1 activation and showed that parthenolide inhibited ERK and AP-1 activation. Using a luciferase promoter assay, our studies showed that parthenolide decreased activation of the IL-8 promoter in CF cells stimulated with TNFα-IL-1β.

ConclusionsIn addition to NFκB MAPKs ERK, JNK and p38 and the transcription factor AP-1 are also dysregulated in CF epithelial cells. Parthenolide inhibited both NFκB and MAPK-AP-1 pathways contributing to the inhibition of IL-8 production.

AbbreviationsCFCystic fibrosis

MAPKsMitogen activated protein kinases

HBECHuman bronchial epithelial cells

ERKExtracellular-regulated protein kinase

JNKJun-N terminal protein kinase


16 HBEhuman bronchial epithelial cell line

AS16HBE stably transfected with antisense oligonucleotides which inhibit expression of CFTR

IB3-1Genetically CF Clinical sample

CFTR-Inhibitor 172CFTRinh-172

Electronic supplementary materialThe online version of this article doi:10.1186-1476-9255-8-26 contains supplementary material, which is available to authorized users.

Melvin Berger and Tracey L Bonfield contributed equally to this work.

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Autor: Aicha Saadane - Jean Eastman - Melvin Berger - Tracey L Bonfield


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