Blocking RhoA/ROCK inhibits the pathogenesis of pemphigus vulgaris by suppressing oxidative stress and apoptosis through TAK1/NOD2-mediated NF-κB pathway

Mol Cell Biochem. 2017 Dec;436(1-2):151-158. doi: 10.1007/s11010-017-3086-x. Epub 2017 Jun 12.

Abstract

Oxidative stress and apoptosis play critical roles in pemphigus vulgaris (PV). The main aim of the present study was to investigate the effects of RhoA/ROCK signaling on UVB-induced oxidative damage, and to delineate the molecular mechanisms involved in the UVB-mediated inflammatory and apoptotic response. In HaCaT cells, we observed that blockage of RhoA/ROCK signaling with the inhibitor CT04 or Y27632 greatly inhibited the UVB-mediated increase in intracellular reactive oxygen species (ROS). Additionally, inhibition of RhoA/ROCK signaling reduced UVB-induced apoptosis, as exemplified by a reduction in DNA fragmentation, and also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic protein Bax, caspase-3 cleavage and decreased PARP-1 protein. The release of inflammatory mediators TNF-α, IL-1β, and IL-6 was also attenuated. Mechanically, we observed that blockage of RhoA/ROCK repressed the TAK1/NOD2-mediated NF-κB pathway in HaCaT cells exposed to UVB. Taken together, these data reveal that RhoA/ROCK signaling is one of the regulators contributing to oxidative damage and apoptosis in human keratinocytes, suggesting that RhoA/ROCK signaling has strong potential to be used as a useful therapeutic target in skin diseases including PV.

Keywords: Apoptosis; Inflammatory response; Oxidative stress; Pemphigus vulgaris (PV); RhoA/ROCK signaling.

MeSH terms

  • Cell Line
  • Humans
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism*
  • Oxidative Stress*
  • Pemphigus / genetics
  • Pemphigus / metabolism*
  • Pemphigus / pathology
  • Signal Transduction*
  • Ultraviolet Rays
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • RHOA protein, human
  • rho-Associated Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • rhoA GTP-Binding Protein