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Published ahead of print on July 18, 2003, doi:10.1165/rcmb.2003-0122OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 3, March 2004, 342-349

A more recent version of this article appeared on March 1, 2004
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Submitted on April 4, 2003
Revised on July 17, 2003

MAP-kinase modulation of NF-{kappa}B-induced GM-CSF release from human alveolar macrophages

Andrea Koch1*, Mark Giembycz2, Kazuhiro Ito2, Sam Lim2, Elen Jazrawi2, Peter J. Barnes2, Ian Adcock2, Erland Erdmann1, and K.Fan Chung2

1 Medizinische Klinik III, Department of Pneumology, University of Cologne, Cologne, Germany, 2 Imperial College at National Heart and Lung Institute, London, United Kingdom

* To whom correspondence should be addressed. E-mail: andrea.koch{at}uni-koeln.de.

Granulocyte/macrophage colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T-cell and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-{kappa}B (NF-{kappa}B), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 µM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression but not by SB 203580 (10 µM), an inhibitor of p38-MAPkinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2 and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-{kappa}B:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-{kappa}B activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 µM), an inhibitor of NF-{kappa}B translocation and the specific IKK-2-Inhibitor (AS602868;10 µM), prevented also GM-CSF expression and release induced by LPS indicating that GM-CSF release is NF-{kappa}B-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-{kappa}B activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.




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