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GM-CSF priming of human monocytes is dependent on ERK1/2 activation

Department of Trauma Surgery, University Hospital of Essen, Essen, Germany

Meenakshi Rani

Surgical Research Group - Trauma Surgery, University Hospital of Essen, Essen, Germany

Christian Selbach

Department of Trauma Surgery, University Hospital of Essen, Essen, Germany

Ernst Kreuzfelder

Department of Immunology, University Hospital of Essen, Essen, Germany

Fritz Ulrich Schade

Surgical Research Group - Trauma Surgery, University Hospital of Essen, Essen, Germany

Sascha Flohé

Department of Trauma Surgery, University Hospital of Essen, Essen, Germany, sascha.flohe{at}uni-essen.de

The ability to augment monocyte functions such as TNF--producing capacities confers a high immunostimulating potential to GM-CSF. In the present investigation, the mechanism of the GM-CSF-mediated enhancement of monocyte cytokine production was analysed with regard to the involvement of intracellular signalling pathways. GM-CSF primes human monocytes dose- and time-dependently for enhanced LPS-stimulated TNF- synthesis. Pre-incubation with 10 ng/ml GM-CSF for 6 h before LPS stimulation (10 ng/ml) caused a 3.4 ± 1.9-fold increase in TNF- release compared to unprimed controls. This was associated with increased phosphorylation of IB and elevated nuclear levels of the NF-B components p50 and p65 and NF-B binding to DNA. LPS-induced AP-1 binding to DNA was also enhanced in GM-CSF-pre-incubated cells. GM-CSF treatment also caused a slight increase in TLR4 expression on monocytes while CD14 expression remained unchanged. GM-CSF-priming was unaffected by inhibitors of p38 MAPK (SB203580) and lipoxygenase (NDGA). In contrast, the broad-spectrum tyrosine kinase inhibitor genistein and the MEK-1 inhibitor (PD98059) abrogated GM-CSF priming of TNF- release and activation of both NF-B and AP-1. It is concluded that a tyrosine kinase of the GM-CSF-triggered ERK1/2 pathway augments the LPS-induced NF-B and AP-1 activation.

Key Words: Cytokines • GM-CSF • lipopolysaccharide • monocytes • signal transduction

Journal of Endotoxin Research, Vol. 12, No. 1, 10-20 (2006)
DOI: 10.1177/09680519060120010201


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