Interleukins involved in the pathogenesis of chronic airway inflammation
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, exposure to it eliciting a broad spectrum of deleterious pathophysiological effects. Since mitogen-activated protein kinase (MAPK) pathways appear to play an important role in both cell survival and the apoptotic process, we assessed the effects of TCDD on the activation of extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK), p38 MAPKs and caspase-3 in RAW 264.7 cells. TCDD treatment induced a transient upshift in ERK activity, followed by a decline, but a concomitant dramatic activation of p38. However, TCDD did not cause any apparent change in the activity of JNK, though it induced an up-regulation in caspase-3 activity. These results demonstrate that the equilibrium between the ERK and p38 pathways is critical to the fate of the cells, and that the activation of p38, upstream of caspase, plays an important role in the apoptotic process. The data obtained in this study also suggests that TCDD activates the MAPK pathway via an arylhydrocarbon receptor (AhR)-independent mechanism in RAW 264.7 murine macrophages.
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Protein kinase C (PKC) family members are downregulated by chronic activation at the protein level in most cell types. In T84 human epithelial cells 12‐ O ‐tetradecanoyl phorbol 13‐acetate (TPA) caused persistent translocation of PKC δ to the membrane compartment and a 400% increase of PKC δ‐mRNA after 24 h. In contrast, PKC α protein was completely downregulated and its mRNA was decreased to 60% of control levels after 24 h. This is the first report of PKC δ‐mRNA upregulation by TPA which was previously only shown for PKCβ. In view of the antimitogenic actions of PKC δ this pattern of regulation may serve to preserve growth control even in the presence of chronic cell activation.
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Histone H2B
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Protein kinase C, a family of serine-threonine protein kinases, mediates a variety of intracellular signaling events. Here, the regulatory effect of phorbol 12-myristate 13-acetate(PMA)on the several PKC isozymes in the human lung carcinoma cells A-549 was studied. The expression of PKC-alpha PKC-betaII PKC-gamma PKC-delta and PKC-epsilon in A-549 cells was examined. No detectable PKC-zeta was observed. Short-term treatment of cells with PMA led to the translocation of these PKC isozymes, to different extent, from cytosol to cell membrane. Whereas, prolonged treatment of cells with PMA pronouncedly reduced the levels of PKC-alpha PKC-gamma PKC-delta and PKC-epsilon, but the intracellular level of PKC-betaII was not affected. Furthermore, PMA was observed to have differential effects on the down-regulation of PKC isozymes located in the cytosol and of those located in the membrane. Prolonged PMA treatment caused extensive decrease in the levels of cytosolic PKC-delta and PKC-gamma, and depleted cytosolic PKC-alpha and PKC-betaII. However, the amount levels of membrane PKC-alpha PKC-betaII PKC-gamma PKC-delta isozymes were not decreased. In contrast, PKC-epsilon in both cytosol and membrane fraction was obviously down-regulated by prolonged PMA treatment. This study provided novel evidence on the PMA-mediated activation and down-regulation of different PKC isozymes, which might be helpful in deepening our understanding on the roles of PKC activation and the alterations of their intracellular levels in processes of chemical carcinogenesis.
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BACKGROUND: The effects of aging on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signaling molecules which may be of particular importance in mediating numerous cellular responses including control of cell growth, differentiation and adaptation are the proteins associated with the mitogen activated protein kinase (MAPK) signaling systems. Further MAPKs have emerged as critical components for regulating numerous mechanotrasductive cellular responses. Previous reports have suggested that agng impairs biaxial-loading induced MAPK phosphorylation. How agigng may affect uniaxial mechanotrasductive processes is not clear. PURPOSE: Here we investigate the ability of a uniaxial stretch activate MAPK pathways in adult (6 mo old), aged (30 mo old) and very aged (36 mo old) Fischer 344 x Brown Norway rats. METHODS: Aortea of adult (6 month), aged (30 month), and very aged (36 month) Fischer 344/NNiaHSD X Brown Norway / BiNia rats were subjected to acute bout of a 20% uniaxial stretch. MAPK protein expression, basal phosphorylation and the uniaxial stretch induced changes in phosphorylation were evaluated by immunoblotting. RESULTS: Western blotting of the MAPK family proteins extracellular signal-regulated kinase (ERK) 1/2, p38-, and c-Jun NH2-terminal kinase (JNK)-MAPKs showed differential expression and basal activation between these proteins with age, with notably higher phosphorylation in ERK1/2 and JNK compared to the 6 month aniumals. However, an acute bout of a 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of ERK 1/2 MAPK, p38-, and JNK MAPK. CONCLUSIONS: These observations confirm previous data demonstrating MAPK proteins are mechanically regulated, and in addition, suggest that MAPK signaling following uniaxial stretch is not altered with aging. Taken together, these data may help explain the age related changes in vascular morphology, function and response to injury. (Supported by funds from NSF Grant #0314742)
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We evaluated the role of protein kinase-C (PKC) during insulin action in HIRC-B cells. Insulin provoked rapid increases in 1) diacylglycerol; 2) translocation of PKC epsilon, but not PKC alpha, PKC delta, or PKC zeta, from the cytosol to the membrane fraction; 3) membrane PKC enzyme activity; and 4) phosphorylation of immunoprecipitable 80-kilodalton (kDa) myristylated alanine-rich C-kinase substrate (MARCKS) protein and heat-stable 80-kDa protein (also probably MARCKS). Phorbol esters stimulated the translocation of PKC alpha and PKC delta as well as PKC epsilon, but not PKC zeta. The effects of phorbol esters on 80-kDa MARCKS phosphorylation were approximately 4 times as strong as those of insulin. Treatment of HIRC-B cells with phorbol esters for 20-24 h resulted in complete loss of immunoreactive PKC alpha and PKC delta in cytosol and membrane fractions, but substantial amounts of PKC epsilon were persistently translocated to the membrane fraction of down-regulated cells. This persistently translocated, residual PKC epsilon in down-regulated cells was associated with increased basal hexose uptake, but this was not due to PKC activation, as it was not inhibited by the PKC inhibitor, RO 31-8220. Acute insulin treatment, on the other hand, increased hexose uptake in down-regulated cells, and this insulin-stimulated uptake was inhibited by RO 31-8220 in down-regulated cells as well as in nondown-regulated cells. Insulin also stimulated the phosphorylation of the heat-stable 80-kDa protein in down-regulated cells, suggesting that the residual PKC epsilon in these cells can be activated by insulin.
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Objective To investigate the expression of the phosphorylation of p38 Mitogen-activated protein kinases (p38MAPK) induced by angiotensin Ⅱ (Ang Ⅱ) in human umbilical vein endothelial ceils (HUVECs). Methods Cultured HUVECs were separatedly incubated for 16h with non-stimulators:different time point (0,5,10, 15,30,45,60min) of the observation group with Ang Ⅱ of 100 nmol/L; different dose of Ang Ⅱ(0,10,100,1000,10 000 nmol/L) with a fixed stimulation time of 15 min; Ang Ⅱ + the specific inhibitors of Ang Ⅱ,SB202190.The expression of the phosphorylation of p38MAPK was determined by Western blot.Results Following excitation by Ang Ⅱ(100 nmol/ L),there was substantial up-regulation of p38MAPK phosphorylation in HUVECs with maximal activation at 15-30 min (2.25±0.21,2.51±0.16,P0.005); Ang Ⅱ increased the expression of the phosphorylation of p38MAPK in a dosedependent manner; Pre-treatment with SB202190 (1000,5000 nmol/L) for 30 min before Ang Ⅱ (100 nmol/L)was used, the expression of phosphorylation of p38MAPK was inhibited markedly in a dose-dependent manner.The inhibition rate was 53.9% (P0.01) in SB202190 (5000 nmol/L) group.Conclusions Ang Ⅱ can activate the expression of the phosphorylation of p38MAPK in HUVECs,then induce the inflammation.
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AIM:To investigate the apoptotic effect of cepharanthine(CEP)on neonatal rat cardiomyocytes (NRCMs)and the underlying mechanisms.METHODS:MTT assay was used to detect the viability of the cells.CEP-induced apoptosis in NRCMs was evaluated by Hoechst 33342 staining and the expression of activated caspase-3.The phosphorylation levels of mitogen-activated protein kinases(MAPKs),such as extracellular signal-regulated kinase (ERK),c-jun N-terminal kinase(JNK)and p38 MAPK,were examined by Western blotting.The specific inhibitors of ERK and p38 MAPK were applied for identifying the roles of the corresponding signal pathways in CEP-induced apoptosis of cardiomyocytes.RESULTS:CEP inhibited the viability of NRCMs in a dose-and time-dependent manners.Positive nuclear fragmentation and activated caspase-3 were found in CEP-treated NRCMs.The phosphorylation levels of ERK and p38 MAPK were significantly elevated in CEP-treated NRCMs,but the change of JNK was not obvious.SB203580, an inhibitor of p38 MAPK,significantly alleviated the apoptotic effect induced by CEP.However,PD98059,an inhibitor of ERK1/2,did not significantly reduce the apoptotic effect.CONCLUSION:p38 MAPK is involved in CEP-induced apoptosis in NRCMs.
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