The Study on Signal Mechanism of Protein Kinase C zeta-involved NF-?B Activation in LPS-stimulated TLR4 Signaling Pathways
Abstract (Summary)NF-?B is a key transcription factor mediating a wide spectrum of innate immune responses induced by bacterial lipopolysaccharide (LPS). Although LPS activating NF-?B through TLR4-TRAF6-IKK signaling cascade has been extensively studied, the detailed signal transduction pathways induced by LPS that lead to NF-?B activation, still need to be defined. Recently we found that atypical PKC? is involved in LPS-induced activation of NF-?B in macrophages. LPS induces time-dependent activation of PKC?, and blocking PKC? activity by PKC? pseudosubstrate inhibitor or siRNA effectively inhibits LPS-induced NF-kB activation. Co-immunoprecipitation with anti-PKC? antibody indicates association between PKCand TRAF6 or TAK1. PKC? activity is TRAF6-dependent because inhibition of TRAF6 by transfection with siRNA and dominant-negative mutant attenuates LPS-induced PKC? activation. Furthermore, PKC? activating NF-?B is mediated by TAK1, which is supported by the observation that inhibition of PKC? impairs activation of TAK1 and knock-down of TAK1 attenuates the activation of NF-?B induced by constitutively active PKC?. The results demonstrate a signaling pathway involving PKC?, present in LPS/TLR4-induced NF-?B activation, and the function of PKC? is TRAF6-dependent and mediated by TAK1.
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:innate immunity nf ?b tlr lps pkc?
Date of Publication:01/01/2007