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Mitogen-Activated Protein Kinase Modulation of Nuclear Factor-B–Induced Granulocyte Macrophage–Colony-Stimulating Factor Release from Human Alveolar Macrophages

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

Address correspondence to: Dr. Andrea Koch, University of Cologne, Medizinische Klinik III, Department of Pneumology, Joseph-Stelzmann-Str. 9, 50924 Köln (Cologne), Germany. 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-B (NF-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 the expression of GM-CSF was not inhibited by SB 203580 (10 µM), an inhibitor of p38-MAP kinase. 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-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-B activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 µM), an inhibitor of NF-B translocation and the specific IKK-2-Inhibitor (AS602868; 10 µM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-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-B activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.

Abbreviations: activator protein-1, AP-1 • bronchoalveolar lavage fluid, BALF • bovine serum albumin, BSA • dithiothreitol, DTT • enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • extracellular signal–regulated kinase, ERK • fetal calf serum, FCS • granulocyte macrophage–colony-stimulating factor, GM-CSF • histone acetyltransferase, HAT • histone deacetylase, HDAC • horseradish peroxidase, HRP • interleukin, IL • c-jun N-terminal kinase, JNK • lipopolysaccharide, LPS • mitogen-activated protein kinase, MAPK • MAP kinase kinase, MKK • 3-(4,5-dimethylthiazol-2-yl)-2,5dephenyltetrazolium bromide, MTT • nuclear factor B, NF-B • phenylmethylsulfonyl fluoride, PMSF • tumor necrosis factor , TNF-

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