A novel protein kinase C (PKCepsilon) is required for fMet-Leu-Phe-induced activation of NF-kappaB in human peripheral blood monocytes.
We have reported that the chemoattractant, fMet-Leu-Phe (fMLP), induces the activation of NF-kappaB 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, PKCepsilon, associates functionally with RhoA in fMLP-stimulated monocytes and that PKCepsilon acted as a signaling component downstream of the GTPase RhoA during fMLP-induced activation of NF-kappaB. Stimulation of monocytes with fMLP resulted in activation of both PKCepsilon and NF-kappaB. This latter activation was largely blocked by specific inhibitors of PKCepsilon by transient expression of a dominant-negative form of PKCepsilon and by PKCepsilon-specific short interfering RNA. These findings demonstrate, for the first time, that fMLP-induced activation of NF-kappaB utilizes a signaling pathway, which requires activity of PKCepsilon, and that PKCepsilon 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-PKCepsilon-NF-kappaB 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.
Chen
Ling-Yu
LY
Department of Medicine, and Department of Medical Microbiology and Immunology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614, USA.
Doerner
Astrid
A
Lehmann
Paul F
PF
Huang
Shuang
S
Zhong
Guangming
G
Pan
Zhixing K
ZK
D004789:Enzyme Activation; D005799:Genes, Dominant; D006801:Humans; D051550:I-kappa B Kinase; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation; D008156:Luciferases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D016328:NF-kappa B; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D009240:N-Formylmethionine Leucyl-Phenylalanine; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020742:rhoA GTP-Binding Protein