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Mol Immunol. 2011 Dec;49(3):415-22. doi: 10.1016/j.molimm.2011.08.005. Epub 2011 Sep 6.

MAPK/AP-1 activation mediates TLR2 agonist-induced SPLUNC1 expression in human lung epithelial cells.

Author information

1
Department of Medicine, National Jewish Health, University of Colorado Denver, Denver, CO 80206, USA.

Abstract

BACKGROUND:

Short Palate Lung and Nasal epithelium Clone 1 (SPLUNC1) is a newly described host defense protein, primarily expressed in large airway epithelial cells. Reduced SPLUNC1 has been reported in allergic and cigarette smoke-exposed airways. We found that Mycoplasma pneumoniae increases SPLUNC1 in airway epithelium in part via activating TLR2-NF-κB pathway. However, the contribution of additional signaling pathways to TLR2-mediated SPLUNC1 expression remains unclear. In the present study, we investigated if TLR2-induced mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling regulates SPLUNC1 expression in human lung epithelial cells.

METHODS:

Human lung epithelial NCI-H292 cells were stimulated with a TLR2 agonist Palmitoyl (3)-Cys-Ser-Lys (4)-OH (Pam(3)CSK(4)). MAPK/AP-1 activation and its role in SPLUNC1 regulation were investigated by Western blot, c-Jun activation assay, chromatin immunoprecipitation (ChIP) and real-time PCR. SPLUNC1 promoter activity was assessed by a luciferase reporter assay.

RESULTS:

Pam(3)CSK(4) increased SPLUNC1 expression in NCI-H292 cells in a dose- and time-dependent manner, and enhanced SPLUNC1 promoter activity. Pam(3)CSK(4)-treated cells demonstrated activated MAPK and c-Jun compared to untreated cells. ChIP assay indicated increased c-Jun binding to the SPLUNC1 promoter following Pam(3)CSK(4) stimulation. Inhibition of ERK1/2 significantly reduced Pam(3)CSK(4)-mediated c-Jun activation and SPLUNC1 expression.

CONCLUSIONS:

Our results for the first time demonstrate that TLR2-mediated MAPK/AP-1 activation up-regulates lung epithelial SPLUNC1 expression at the transcriptional level. Understanding SPLUNC1 gene regulation should provide more specific therapeutic targets to restore deficient SPLUNC1 production in diseased airways.

PMID:
21899893
PMCID:
PMC3224182
DOI:
10.1016/j.molimm.2011.08.005
[Indexed for MEDLINE]
Free PMC Article
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