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Selected Works of Richard S. Beard Jr.
Article
Interleukin-1β-Induced Barrier Dysfunction Is Signaled Through PKC-θ in Human Brain Microvascular Endothelium
American Journal of Physiology - Cell Physiology (2012)
  • Robert R. Rigor, University of California at Davis
  • Richard S. Beard, Jr., University of South Florida
  • Olesya P. Litovka, University of California at Davis
  • Sarah Y. Yuan, University of South Florida
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Abstract
Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1β is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1β exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1β triggered activation of novel PKC isoforms δ, μ, and θ, followed by decreased transendothelial electrical resistance (TER). The IL-1β-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-θ or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-θ. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1β treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC-θ-dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1β is a central inflammatory mediator, our interpretation is that inhibition of PKC-θ or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.
Keywords
  • neuroinflammatory conditions,
  • edema,
  • blood-brain barrier,
  • microvascular permeability,
  • tight junction proteins
Disciplines
Publication Date
May 15, 2012
DOI
10.1152/ajpcell.00371.2011
Citation Information
Robert R. Rigor, Richard S. Beard, Olesya P. Litovka and Sarah Y. Yuan. "Interleukin-1β-Induced Barrier Dysfunction Is Signaled Through PKC-θ in Human Brain Microvascular Endothelium" American Journal of Physiology - Cell Physiology Vol. 302 Iss. 10 (2012) p. C1513 - C1522
Available at: http://works.bepress.com/richard-beard/20/