Student Research: William Polk

, Environmental Toxicology (Tox), 2006
Faculty Advisor: James S. Woods

Role of Protein Kinase C Zeta in Lipopolysaccharide-Mediated Nuclear Factor kappa B Activation and Transcriptional Activity in Kidney Epithelial Cells


Abstract

NF-κB is a critical transcription factor that mediates cellular responses to invading pathogens. In the kidney, NF-κB’s most important targets are the cytokines and chemokines, which regulate the scale of the inflammatory response by recruiting and facilitating immunocyte activity in the kidney, especially polymorphonuclear leukocytes. For induction of these genes, NF-κB must be translocated from the cytoplasm to the nuclear compartment, bind nuclear κB consensus elements and induce RNA polymerase loading at these sites.

In this work we show that in kidney proximal tubule cells, PKCς acts upstream of multiple phases of the NF-κB activation, and is a determinant of the profile of cytokines induced in response to LPS. We show that PKCς interacts with the IKK complex directly and that inhibition of the PKCς’s catalytic activity with either pharmacologic inhibitors or over expression of a dominant negative PKCς blocks IKK activity and subsequent NF-κB DNA binding. We also show that PKCς regulates NF-κB transactivation not only through direct phosphorylation of serine 311 on p65, but also through a novel regulatory mechanism associated with p300 activation. The culmination of PKCς activity is a shift in the expression of NF-κB driven genes away from the proinflammatory genes, TNFα and Cox-2, to the inflammatory resolution genes IL-6 and A20.