An Atypical Protein Kinase C (PKCζ) Plays a Critical Role in Lipopolysaccharide-Activated NF-κB in Human Peripheral Blood Monocytes and Macrophages

Huang, Xue; Chen, Ling Yu; Doerner, Astrid M.; Pan, Warren; Smith, Laura A.; Huang, Shuang; Papadimos, Thomas J.; Pan, Zhixing K.

doi:10.4049/jimmunol.0804073

Cited by 45 publications

(35 citation statements)

References 40 publications

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“…Thus, PKC can directly associate with and efficiently phosphorylate RelA, and, more importantly, TNF-␣-induced phosphorylation of RelA in vivo was shown to be dramatically inhibited in pkc Ϫ/Ϫ embryonic fibroblasts (34). Moreover, PKC has also been implicated in LPS-induced NF-B activation within human peripheral blood monocytes and macrophages through its association with both RhoA and activating transforming growth factor ␤-activated kinase-1 (TAK1) (36). Our findings also implicate a role for PKC in TNF signaling in airway epithelial cells.…”

Section: Discussionsupporting

confidence: 61%

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

Choudhary

Rosenblatt

Fang

et al. 2011

Journal of Biological Chemistry

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Nuclear factor-B (NF-B) is an inducible cytoplasmic transcription factor that plays a role as a master regulator of airway mucosal inflammation. The prototypical ("canonical") NF-B pathway controls cytoplasmic to nuclear translocation in response to stimulation by the mononuclear cytokine, TNF. Despite intensive investigation, the spectrum of kinases involved in the canonical NF-B pathway has not yet been systematically determined. Here we have applied a high throughput siRNA-mediated loss-of-function screening assay to identify novel kinases important in TNF-induced NF-B signaling. Type II A549 epithelial cells stably expressing an IL-8/luciferase reporter gene optimized for high throughput siRNA format (Z score of 0.65) and siRNAs for 636 human kinases were reversetransfected and screened in the assay. 36 candidate genes were identified that inhibited TNF signaling with a Z score deviation of <؊1.3 in replicate plates. From this group, 11 kinases were selected for independent validation, of which eight were successfully silenced. Six kinases were validated, including ATM, CDK2, -5, and -7, CALM3, MAPAKP5, and MAP3K/MEKK3. The surprising function of ATM in TNF signaling was confirmed where reduced NF-B/RelA translocation and Ser-276 phosphorylation were seen in ATM ؊/؊ mouse embryo fibroblasts. These data indicate that ATM is a key regulatory kinase that may control global NF-B activation in the TNF-induced canonical pathway.Eukaryotic tissues respond to signals in their extracellular environment through the induction of long term phenotypic plasticity. An important mechanism for this plasticity is through the activation of cell surface receptors coupled to intracellular signal transduction networks, the activation of which, in turn, induces a reactive gene expression. One specific example occurs in airway mucosal surfaces that normally promote gas exchange, facilitate particulate matter clearance through the muco-ciliary escalator, and protect against oxidative damage (1). Within this surface, sentinel epithelial cells are responsible for activating the innate inflammatory response upon stimulation with macrophage-derived cytokines via the plasma membrane-anchored TNF/death receptor (TNFR) 2 superfamily (2, 3). Liganded TNFRs signal intracellularly through nuclear factor-B (NF-B), an inducible cytoplasmic transcription factor that temporally coordinates expression of gene networks, including interferon, cytokine, and anti-apoptotic genes (4 -6). As a result, the mucosal surface assumes a pathogen-resistant and proinflammatory phenotype. Because of its central role in airway inflammatory disease, the NF-B signaling pathway has been extensively investigated.Under resting conditions, NF-B is inhibited in the cytoplasm by binding to members of the IB family of inhibitory proteins, resulting in cytoplasmic retention and inactivation of its latent DNA binding activity. TNFR-ligand binding results in submembranous recruitment of death domains containing adapter molecules, including the TNF receptor-associated factors...

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Section: Discussionsupporting

confidence: 61%

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

Choudhary

Rosenblatt

Fang

et al. 2011

Journal of Biological Chemistry

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“…PKC (as well as PKC␦ and PKC) activity is increased seven-to eightfold by 5 min after TNF-␣ challenge (550). Finally Rac1 is activated (796). NOX2 requires active Rac1 (297) as well as phosphorylation of the p47 phox regulatory subunit, probably by PKC (796).…”

Section: Mapk Mapk Targets and Atherosclerosismentioning

confidence: 99%

“…Finally, targeting of IB proteins by IKK1/2 leads to transcription factor activation. The pathways even share several common MAP4K (such PKC) (87,796).…”

Section: Mapk Mapk Targets and Atherosclerosismentioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…Antioxidants interact directly with and neutralize ROS which have been used to reverse oxidant-mediated pulmonary injury. Protection from endotoxin-induced inflammation may be mediated by the inhibition of atypical protein kinase C (aPKC) which is an enzyme critical to NF-κB activation by LPS in macrophages (Huang et al, 2009). Therefore, it is expected that MSCs reduce MUC5AC production through an antioxidant mechanisms.…”

Section: Mucin Rmuc-5ac Gene Expression In Lung Tissuementioning

confidence: 99%

Impact of Mesenchymal Stem Cells on Lipopolysaccharide-Induced Apoptosis in Acute Lung Injury Rat Model

Mansour¹,

Soliman²,

Hasan³

et al. 2018

Int.J.Curr.Microbiol.App.Sci

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An Atypical Protein Kinase C (PKCζ) Plays a Critical Role in Lipopolysaccharide-Activated NF-κB in Human Peripheral Blood Monocytes and Macrophages

Cited by 45 publications

References 40 publications

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

Molecular Biology of Atherosclerosis

Impact of Mesenchymal Stem Cells on Lipopolysaccharide-Induced Apoptosis in Acute Lung Injury Rat Model

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