A novel protein kinase C (PKCε) is required for fMet-Leu-Phe-induced activation of NF-κB in human peripheral blood monocytes

We have reported that the chemoattractant, fMet-Leu-Phe (fMLP), induces the activation of NF-κB in human peripheral blood monocytes and that this requires the activity of small GTPase, RhoA (Huang, S., Chen, L.-Y., Zuraw, B. L., Ye, R. D., and Pan, Z. K. (2001) J. Biol. Chem. 276, 40977-40981). Here we showed that the novel protein kinase C isozyme, PKCε, associates functionally with RhoA in fMLP-stimulated monocytes and that PKCε acted as a signaling component downstream of the GTPase RhoA during fMLP-induced activation of NF-κB. Stimulation of monocytes with fMLP resulted in activation of both PKCε and NF-κB. This latter activation was largely blocked by specific inhibitors of PKCε by transient expression of a dominant-negative form of PKCε and by PKCε-specific short interfering RNA. These findings demonstrate, for the first time, that fMLP-induced activation of NF-κB utilizes a signaling pathway, which requires activity of PKCε, and that PKCε acts as a signaling component downstream of RhoA in cytokine gene transcription stimulated by a chemoattractant. The specificity of this response suggests an important role for the Rho GTPase-PKCε-NF-κB pathway in host defense and represents a novel and potentially important mechanism through which fMLP not only attracts leukocytes but may also contribute directly to inflammation.