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PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds

  • Authors:
    • Jian Zhang
    • Xuekang Yang
    • Hongtao Wang
    • Bin Zhao
    • Xue Wu
    • Linlin Su
    • Songtao Xie
    • Yunchuan Wang
    • Jun Li
    • Jiaqi Liu
    • Mengdong Liu
    • Fu Han
    • Ting He
    • Wei Zhang
    • Ke Tao
    • Dahai Hu
  • View Affiliations / Copyright

    Affiliations: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1335-1346
    |
    Published online on: September 20, 2017
       https://doi.org/10.3892/ijmm.2017.3144
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Abstract

Protein kinase Cζ (PKCζ) is a member of the atypical protein kinase C family. Its roles in macrophages or skin-resident keratinocytes have not been fully evaluated. In this study, we provide evidence that PKCζ mediates lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) gene expression in the mouse macrophage cell line, RAW264.7. TNFα has been proven to be one of the main culprits of chronic wounds and impaired acute wounds, which are characterized by excessive inflammation, enhanced proteolysis and reduced matrix deposition. Among the multiple effects of TNFα on keratinocytes, the induction of chemokines which are indispensable factors involved in the massive infiltration of various inflammatory cells into skin lesions serves as a crucial mechanism. In the present study, we found that PKCζ inhibitor or its specific siRNA inhibited the TNFα-induced upregulation in the levels of the chemokines, interleukin (IL)-8, monocyte chemotactic protein-1 (MCP-1) and intercellular cell adhesion molecule-1 (ICAM-1) in HaCaT keratinocytes. Moreover, under a disrupted inflammatory environment, activated keratinocytes can synthesize large amounts of matrix metalloproteinases (MMP), which has a negative effect on tissue remodeling. We discovered that TNFα promoted the expression of MMP9 in a PKCζ-dependent manner. Further experiments revealed that nuclear factor-κB (NF-κB) was a key downstream molecule of PKCζ. In addition, as shown in vitro, PKCζ was not involved in the TNFα-induced decrease in HaCaT cell migration and proliferation. In vivo experiments demonstrated that TNFα-induced wound closure impairment and inflammatory disorders were significantly attenuated in the PKCζ inhibitor group. On the whole, our findings suggest that PKCζ is a crucial regulator in LPS- or TNFα-induced inflammatory responses in RAW264.7 cells and HaCaT keratinocytes, and that PKCζ/NF-κB signaling may be a potential target for interventional therapy for TNFα-induced skin inflammatory injury.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang J, Yang X, Wang H, Zhao B, Wu X, Su L, Xie S, Wang Y, Li J, Liu J, Liu J, et al: PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds. Int J Mol Med 40: 1335-1346, 2017.
APA
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L. ... Hu, D. (2017). PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds. International Journal of Molecular Medicine, 40, 1335-1346. https://doi.org/10.3892/ijmm.2017.3144
MLA
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L., Xie, S., Wang, Y., Li, J., Liu, J., Liu, M., Han, F., He, T., Zhang, W., Tao, K., Hu, D."PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds". International Journal of Molecular Medicine 40.5 (2017): 1335-1346.
Chicago
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L., Xie, S., Wang, Y., Li, J., Liu, J., Liu, M., Han, F., He, T., Zhang, W., Tao, K., Hu, D."PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds". International Journal of Molecular Medicine 40, no. 5 (2017): 1335-1346. https://doi.org/10.3892/ijmm.2017.3144
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang J, Yang X, Wang H, Zhao B, Wu X, Su L, Xie S, Wang Y, Li J, Liu J, Liu J, et al: PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds. Int J Mol Med 40: 1335-1346, 2017.
APA
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L. ... Hu, D. (2017). PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds. International Journal of Molecular Medicine, 40, 1335-1346. https://doi.org/10.3892/ijmm.2017.3144
MLA
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L., Xie, S., Wang, Y., Li, J., Liu, J., Liu, M., Han, F., He, T., Zhang, W., Tao, K., Hu, D."PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds". International Journal of Molecular Medicine 40.5 (2017): 1335-1346.
Chicago
Zhang, J., Yang, X., Wang, H., Zhao, B., Wu, X., Su, L., Xie, S., Wang, Y., Li, J., Liu, J., Liu, M., Han, F., He, T., Zhang, W., Tao, K., Hu, D."PKCζ as a promising therapeutic target for TNFα-induced inflammatory disorders in chronic cutaneous wounds". International Journal of Molecular Medicine 40, no. 5 (2017): 1335-1346. https://doi.org/10.3892/ijmm.2017.3144
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