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

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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.

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Acknowledgments

The authors of this study would like to thank Eric Kopfle, Alex Miller, and Sindhuja Surapeneni for assistance with data collection. This work was funded by Georgia Tech startup funds and NIH New Innovator grant #1DP2OD007433-01 (MOP). The project described was supported by Award Number DP2OD007433 from the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Office of the Director, National Institutes of Health or the National Institutes of Health. PMK was supported by an NSF graduate research fellowship.

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  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Dr. Suite 1308, Atlanta, GA, 30332, USA

    Philip M. Keegan, Catera L. Wilder & Manu O. Platt

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  1. Philip M. Keegan
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  2. Catera L. Wilder
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  3. Manu O. Platt
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Correspondence to Manu O. Platt.

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Keegan, P.M., Wilder, C.L. & Platt, M.O. Tumor necrosis factor alpha stimulates cathepsin K and V activity via juxtacrine monocyte–endothelial cell signaling and JNK activation. Mol Cell Biochem 367, 65–72 (2012). https://doi.org/10.1007/s11010-012-1320-0

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  • DOI: https://doi.org/10.1007/s11010-012-1320-0

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