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Int. J. Mol. Sci. 2017, 18(10), 2163;

The Specific Mitogen- and Stress-Activated Protein Kinase MSK1 Inhibitor SB-747651A Modulates Chemokine-Induced Neutrophil Recruitment

Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Author to whom correspondence should be addressed.
Received: 29 August 2017 / Revised: 4 October 2017 / Accepted: 14 October 2017 / Published: 17 October 2017
(This article belongs to the Special Issue Cell-cell Interactions in Blood Vessels)
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Mitogen-activated protein kinase (MAPK) signaling is involved in a variety of cellular functions. MAPK-dependent functions rely on phosphorylation of target proteins such as mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 participates in the early gene expression and in the production of pro- and anti-inflammatory cytokines. However, the role of MSK1 in neutrophil recruitment remains elusive. Here, we show that chemokine macrophage inflammatory protein-2 (CXCL2) enhances neutrophil MSK1 expression. Using intravital microscopy and time-lapsed video analysis of cremasteric microvasculature in mice, we studied the effect of pharmacological suppression of MSK1 by SB-747651A on CXCL2-elicited neutrophil recruitment. SB-747651A treatment enhanced CXCL2-induced neutrophil adhesion while temporally attenuating neutrophil emigration. CXCL2-induced intraluminal crawling was reduced following SB-747651A treatment. Fluorescence-activated cell sorting analysis of integrin expression revealed that SB-747651A treatment attenuated neutrophil integrin αMβ2 (Mac-1) expression following CXCL2 stimulation. Both the transmigration time and detachment time of neutrophils from the venule were increased following SB-747651A treatment. It also decreased the velocity of neutrophil migration in cremasteric tissue in CXCL2 chemotactic gradient. SB-747651A treatment enhanced the extravasation of neutrophils in mouse peritoneal cavity not at 1–2 h but at 3–4 h following CXCL2 stimulation. Collectively, our data suggest that inhibition of MSK1 by SB-747651A treatment affects CXCL2-induced neutrophil recruitment by modulating various steps of the recruitment cascade in vivo. View Full-Text
Keywords: MSK1; SB-747651A; neutrophil recruitment; intravital microscopy; chemokine MSK1; SB-747651A; neutrophil recruitment; intravital microscopy; chemokine

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Hossain, M.; Omran, E.; Xu, N.; Liu, L. The Specific Mitogen- and Stress-Activated Protein Kinase MSK1 Inhibitor SB-747651A Modulates Chemokine-Induced Neutrophil Recruitment. Int. J. Mol. Sci. 2017, 18, 2163.

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