Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human beta-defensin 2 in middle ear epithelial cellsReportar como inadecuado

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BMC Infectious Diseases

, 6:12

First Online: 24 January 2006Received: 05 August 2005Accepted: 24 January 2006


BackgroundWe recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae NTHi and that interleukin 1 alpha IL-1 alpha up-regulates the transcription of beta-defensin 2 DEFB4 according to new nomenclature of the Human Genome Organization in human middle ear epithelial cells via a Src-dependent Raf-MEK1-2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components.

MethodsThe studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media OM. Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or beta-defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the beta-defensin 2 promoter was monitored using a beta-defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction.

ResultsMiddle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine-paracrine synergistic manner with NTHi to up-regulate beta-defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced beta-defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway.

ConclusionWe demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate beta-defensin 2 via the p38 MAP kinase pathway.

List of abbreviationsOMotitis media

NTHinontypeable Haemophilus influenzae

TLRtoll-like receptor


MAP kinasemitogen-activated protein kinase


ERKextracellular signal-regulated kinase

DEFBhuman beta-defensin

IPinterferon-γ-inducible protein

RANTESregulated upon activation, normally T-expressed, and presumably secreted

MIPmacrophage inflammatory protein

HMEEChuman middle ear epithelial cell line

IKKI-kappa-B kinase

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2334-6-12 contains supplementary material, which is available to authorized users.

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Autor: Sung-Kyun Moon - Haa-Yung Lee - Huiqi Pan - Tamotsu Takeshita - Raekil Park - Kiweon Cha - Ali Andalibi - David J Lim


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