Molecular and Cellular Biochemistry

, Volume 367, Issue 1–2, pp 65–72

Tumor necrosis factor alpha stimulates cathepsin K and V activity via juxtacrine monocyte–endothelial cell signaling and JNK activation

  • Philip M. Keegan
  • Catera L. Wilder
  • Manu O. Platt
Article

Abstract

Inflammation and damage promote monocyte adhesion to endothelium and cardiovascular disease (CVD). Elevated inflammation and increased monocyte–endothelial cell interactions represent the initial stages of vascular remodeling associated with a multitude of CVDs. Cathepsins are proteases produced by both cell types that degrade elastin and collagen in arterial walls, and are upregulated in CVD. We hypothesized that the inflammatory cytokine tumor necrosis factor alpha (TNFα) and monocyte binding would stimulate cathepsins K and V expression and activity in endothelial cells that may be responsible for initiating local proteolysis during CVD. Confluent human aortic endothelial cells were stimulated with TNFα or THP-1 monocyte co-cultures, and multiplex cathepsin zymography was used to detect changes in levels of active cathepsins K, L, S, and V. Direct monocyte–endothelial cell co-cultures stimulated with TNFα generated maximally observed cathepsin K and V activities compared to either cell type alone (n = 3, p < 0.05) by a c-Jun N-terminal kinase (JNK)-dependent manner. Inhibition of JNK with SP6000125 blocked upregulation of cathepsin K activity by 49 % and cathepsin V by 81 % in endothelial cells. Together, these data show that inflammatory cues and monocyte–endothelial cell interactions upregulate cathepsin activity via JNK signaling axis and identify a new mechanism to target toward slowing the earliest stages of tissue remodeling in CVD.

Keywords

Cathepsins Atherosclerosis Monocytes Endothelial cells Inflammation 

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Philip M. Keegan
    • 1
  • Catera L. Wilder
    • 1
  • Manu O. Platt
    • 1
  1. 1.Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of Technology and Emory UniversityAtlantaUSA

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