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Originally published online as doi:10.1189/jlb.0107009 on June 22, 2007

Published online before print June 22, 2007
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(Journal of Leukocyte Biology. 2007;82:619-629.)
© 2007 by Society for Leukocyte Biology

Molecular mechanisms of thrombin-induced interleukin-8 (IL-8/CXCL8) expression in THP-1-derived and primary human macrophages

Lei Zheng and Manuela Martins-Green1

Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, California, USA

1 Correspondence: Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, CA 92521, USA. E-mail: manuela.martins{at}ucr.edu

Under normal conditions, macrophages provide essential innate immune surveillance in tissues. These cells also play key functions during wound healing and in pathological conditions. When macrophages are exposed to thrombin, an enzyme released from leaky blood vessels, they are stimulated to produce inflammatory cytokines, which are critical for wound healing and can also facilitate tumor growth and invasion. Using antibody cytokine arrays, we identified IL-8/CXCL8, a chemokine that plays important functions in inflammation and angiogenesis and consequently in healing and tumor development, as one of the cytokines that is highly stimulated in macrophages by thrombin. Here, we investigated the signal transduction mechanism by which thrombin stimulates IL-8/CXCL8 expression in THP-1-derived and primary human macrophages. We show that JNK is a crucial mediator of the thrombin signaling pathways in macrophages, and the activation of JNK is dependent on stimulation of the Rho small GTPase. The thrombin-induced Rho/JNK cascade is a novel signaling cascade for IL-8/CXCL8 transcription activation. Understanding the molecular mechanism by which thrombin controls the expression of inflammatory cytokines in macrophages can lead to therapeutic interventions, which can provide better management of healing, inflammation, and tumorigenesis.

Key Words: inflammation • chemokine • Rho • c-jun N-terminal kinase • signal transduction • stress response




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M. L. Petreaca, M. Yao, Y. Liu, K. DeFea, and M. Martins-Green
Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability
Mol. Biol. Cell, December 1, 2007; 18(12): 5014 - 5023.
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