Protein Kinase Cα Regulates Human Monocyte O·̄2Production and Low Density Lipoprotein Lipid Oxidation

Li, Qing; Subbulakshmi, Venkita; Fields, Alan P.; Cathcart, Martha K.

doi:10.1074/jbc.274.6.3764

Cited by 71 publications

(63 citation statements)

References 45 publications

(55 reference statements)

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“…These antisense ODNs were previously characterized and were shown to be selective for their targets in opsonized zymosan-activated human monocytes and not to affect the expression of other isoforms (28). We also characterized these antisense ODN in our system by looking at protein expression by Western blotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

Carnevale

Cathcart

2003

Journal of Biological Chemistry

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Monocyte chemoattractant protein 1 (MCP-1) is important in attracting monocytes to sites of inflammation. Using predominantly pharmacological approaches, prior studies have indicated that serine/ threonine kinases are involved in the MCP-1-induced signaling pathways. We report here that there is substantial inhibition of MCP-1-stimulated chemotaxis of human monocytes treated with inhibitors selective for the subset of serine/threonine kinases, protein kinase C (PKC). Selective inhibitors of PKC such as GF109203X and Calphostin C both caused ϳ80% inhibition of chemotaxis. Because these pharmacological inhibitors do not specifically inhibit individual PKC isoforms, we chose to use antisense oligodeoxyribonucleotides (ODN) to specifically reduce PKC isoform expression, first by inhibiting expression of the conventional PKC family, and next by using specific antisense ODN for PKC␣ and PKC␤. Conventional PKC-antisense ODN treatment completely and significantly inhibited monocyte chemotaxis to MCP-1, whereas sense-control ODN caused no significant inhibition. PKC␤-antisense ODN caused 89.2% inhibition of chemotaxis at its highest dose. In contrast, PKC␤-sense ODN and PKC␣-antisense and -sense ODN were without effect. Further studies evaluating the calcium response that is triggered upon MCP-1 interaction with its receptor, CCR 2 , indicate that this response is not altered by antisense or sense ODN treatment, thus supporting our hypothesis that PKC␤ is critical for post-receptor signal transduction downstream of the immediate calcium signal. These data contribute to our developing understanding of the signal transduction pathways involved in the chemotactic response of human monocytes to MCP-1 and uniquely identify the requirement for the PKC␤ isoform in this important process.

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Section: Resultsmentioning

confidence: 99%

“…Treatment of Cells with ODN-The antisense ODN used in our studies were derived from our prior published work, which reported their efficacy (28,29). The sequence for cPKC-antisense ODN was 5Ј-CCC CAG ATG AAG TCG GTG CA-3Ј, and its control-sense ODN sequence was 5Ј-GGG GTC TAC TTC AGC CAC GT-3Ј.…”

Section: Methodsmentioning

confidence: 99%

Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

Carnevale

Cathcart

2003

Journal of Biological Chemistry

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“…5,11,41 Cellular oxidative modification of cholesterol is thought to involve endothelial-and macrophagederived reactive oxygen species. 36,42,43 Hypertension, which increases arterial wall thickness and oxygen diffusion, produces medial hypoxia and steep oxygen tension gradients within the wall. 44 Recently, compelling evidence was presented that hypoxic areas do indeed exist, particularly in the thickened arterial wall.…”

Section: Discussionmentioning

confidence: 99%

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

et al. 2000

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Abstract-The role of lipid peroxidation during the pathogenesis of atherosclerosis has been described through numerous studies and has provided compelling evidence for free radical-mediated processes that link hypertension with atherosclerosis. However, there remains only limited information concerning peroxidative processes in hypertension and their modulation by antioxidants. In the present study, the formation of cholesterol oxidation products was used as a measure of in vivo lipid peroxidation after hypertension induced by coarctation of the aorta in New Zealand White rabbits. The rabbits were fed a standard chow diet devoid of cholesterol or cholesterol oxidation products such that the measured cholesterol oxides in the plasma and aortic tissues would most plausibly arise from endogenous oxidation of cholesterol. After 12 weeks of hypertension, all of the measured cholesterol oxides increased significantly over baseline levels in the surgically coarctated animals; however, this increase was significantly less in hypertensive probucol-treated animals. Similarly, the cholesterol oxide content of aortic tissue from the surgically coarctated animals was significantly greater than that found in normotensive control aortas, and probucol treatment significantly reduced the increase in cholesterol oxide content of aortic tissue relative to that of hypertensive animals not receiving the antioxidant. These findings in hypertensive animals suggest that cholesterol oxidation products measured in plasma and aortic tissue can be derived from endogenous free radical activity and that this activity is enhanced under specific pathological conditions. (Hypertension. 2000;36:436-441.)

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“…For human monocytes and RAW264.7 macrophages, it has been shown that the primary event, that is, phosphorylation of p47 phox , is facilitated by protein kinase Ca (PKCa). 7,8 Recently, we demonstrated that downregulation of PKCa or expression of a kinase-dead mutant attenuates the PMA-induced oxidative burst. 9 However, the impact of AC on the oxidative burst remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

et al. 2005

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It is appreciated that phagocytosis of apoptotic cells (AC) is an immunological relevant process that shapes the proversus anti-inflammatory macrophage phenotype. It was our intention to study the respiratory burst, a prototype marker of macrophage activation, under the impact of AC. Following incubation of RAW264.7 macrophages with AC, we noticed attenuated production of reactive oxygen species (ROS) in response to PMA treatment, and observed a correlation between attenuated ROS formation and suppression of protein kinase Ca (PKCa) activation. EMSA analysis demonstrated an immediate activation of peroxisome proliferatoractivated receptor-c (PPARc) following supplementation of AC to macrophages. In macrophages carrying a dominantnegative PPARc mutant, recognition of AC no longer suppressed PKCa activation, and the initial phase of ROS formation was largely restored. Interference with actin polymerization and transwell experiments suggest that recognition of AC by macrophages suffices to attenuate the early phase of ROS formation that is attributed to PPARc activation.

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Protein Kinase Cα Regulates Human Monocyte O·̄2Production and Low Density Lipoprotein Lipid Oxidation

Cited by 71 publications

References 45 publications

Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

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