Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells

Perveen, Khalida; Quach, Alex; Stark, Michael J.; Prescott, Susan L.; Barry, Simon C.; Hii, Charles S.; Fèrrante, Antonio

doi:10.3390/ijms222312650

Cited by 9 publications

(8 citation statements)

References 40 publications

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“…In our study, the expression level of heart PRKCA was enhanced, while PRKCE was reduced upon myocardial ischemia, and their levels returned to normal following the pretreatment of XML injection ( Figure 5A ). Approximately, 11 isozymes have been identified in the Protein kinase C (PKC) family ( Perveen et al, 2021 ). PKCα is encoded by the PRKCA gene and is the predominant PKC isoform expressed in the heart ( Aslam, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Putative Prevention of XML Injection Against Myocardial Ischemia Is Mediated by PKC and PLA2 Proteins

Jin

Yin

Mao

et al. 2022

Front. Cell Dev. Biol.

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Background: Xinmailong (XML) injection is a CFDA-approved traditional Chinese medicine with clinical value for heart failure treatment. The present investigation was aimed to evaluate the potential protective roles of this injection on myocardial ischemia and the underlying molecular mechanism.Methods: In our study, we selected two models of myocardial ischemia rats. Rats were randomly divided into six groups, with saline or XML administrated 4 days before ischemia model establishment. ECG of different time intervals and biochemical parameters of end point were measured. The potential mechanisms of the protective role of XML were explored using system pharmacology and molecular biology approaches.Results: Myocardial ischemia rats demonstrated abnormal ECG and serum levels of cTnT. Pretreatment with XML significantly attenuated these damages, especially the medium doses. GO and KEGG analysis revealed that the 90 putative target genes were associated with pathways of fatty acid absorption/metabolism, inflammation, RAAS, and vascular smooth muscle. Further network pharmacology method identified five main chemical ingredients and potential targets of XML injection for myocardial ischemia. Mechanically, the beneficial effect of XML injection was mediated by the reactive oxygen species (ROS) inhibition and inflammation attenuation via regulating the expression levels of targets of PKC and PLA2.Conclusion: These findings indicate that XML exerts protective effects against myocardial injury, with attenuated ROS production, apoptosis, and inflammation. Therefore, we speculate that XML may be an alternative supplementary therapeutic agent for myocardial ischemia prevention.

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Section: Resultsmentioning

confidence: 99%

Putative Prevention of XML Injection Against Myocardial Ischemia Is Mediated by PKC and PLA2 Proteins

Jin

Yin

Mao

et al. 2022

Front. Cell Dev. Biol.

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“…Yang et al, demonstrated an association to prenatal indoor PM 2.5 and tobacco smoke exposure and increased respiratory tract infections in children, potentially modified by maternal Nrf2 status [ 29 ]. Two studies conducted by Perveen et al indicate a correlation in altered cord blood T cells and the risk of the neonate developing allergic-type symptoms later in life [ 30 , 31 ]. These cord blood cells may be the first step in elucidating the priming of the neonatal pulmonary T cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

NRF2 Protects against Altered Pulmonary T Cell Differentiation in Neonates Following In Utero Ultrafine Particulate Matter Exposure

et al. 2022

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Early life exposure to particulate matter (PM) air pollution negatively impacts neonatal health. The underlying mechanisms following prenatal exposure, particularly to ultrafine particles (UFP, diameter ≤ 0.1 μm), are not fully understood; To evaluate the role of Nrf2 in response to in utero UFP exposure, we exposed time-mated Nrf2-deficient (Nrf2−/−) or wildtype (WT) mice to filtered air (FA) or 100 μg/m3 ultrafine PM daily throughout pregnancy. Offspring were evaluated for pulmonary immunophenotypes and pulmonary/systemic oxidative stress on postnatal day 5, a timepoint at which we previously demonstrated viral respiratory infection susceptibility; Nrf2−/− offspring exposed to FA had significantly lower average body weights compared to FA-exposed WT pups. Moreover, PM-exposed Nrf2−/− offspring weighed significantly less than PM-exposed WT pups. Notably, PM-exposed Nrf2−/− offspring showed a decreased pulmonary Th1/Th2 ratio, indicating a Th2 bias. Th17 cells were increased in FA-exposed Nrf2−/− neonates yet decreased in PM-exposed Nrf2−/− neonates. Analysis of oxidative stress-related genes in lung and oxidative stress biomarkers in liver tissues did not vary significantly across exposure groups or genotypes. Collectively, these findings indicate that the lack of Nrf2 causes growth inhibitory effects in general and in response to gestational UFP exposure. Prenatal UFP exposure skews CD4+ T lymphocyte differentiation toward Th2 in neonates lacking Nrf2, signifying its importance in maternal exposure and infant immune responses.

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“…Cord blood T cells were matured using different stimulation methods. In the classical [7] CD3/CD28 co‐stimulation cultures, anti‐CD3 antibody (clone OKT3, Abcam, Cambridge, UK) was added to 24‐well tissue culture plates at a final concentration of 2.5 μg/mL in HBSS and incubated at 4°C overnight or at 37°C for 3 h, and then washed with HBSS. At the initiation of culture, anti‐CD28 antibody (clone CD28.2, eBiosciences, San Diego, CA, USA) was added to a final concentration of 1 μg/mL with 1 × 10 6 CBTC in each well in a final volume of 1 mL.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that lower PKCζ levels in cord blood T cells (CBTC) predict a high risk of developing allergy in the first years of life [3][4][5]. Further, when CBTC with low PKCζ are matured in vitro, those with lower PKCζ expression have a propensity to produce higher Th2 cytokines such as IL-4/ IL-9 and lower interferon-gamma (IFN-γ) [4,6,7]. This relationship between low PKCζ, Th2 propensity and allergic sensitisation is not evident with other PKC isozymes [3,7].…”

Section: Introductionmentioning

confidence: 99%

“…Further, when CBTC with low PKCζ are matured in vitro, those with lower PKCζ expression have a propensity to produce higher Th2 cytokines such as IL-4/ IL-9 and lower interferon-gamma (IFN-γ) [4,6,7]. This relationship between low PKCζ, Th2 propensity and allergic sensitisation is not evident with other PKC isozymes [3,7]. Interestingly, we have shown that early intervention with omega 3 polyunsaturated fatty acids (fish oil) during pregnancy resulted in higher levels of PKCζ and reduced development of allergy in the infants [3], potentially involving epigenetic regulation of the PKCζ gene through the acetylation of histone H3 [8].…”

Section: Introductionmentioning

confidence: 99%

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PKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN‐γ propensity

et al. 2023

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A significant number of babies present transiently with low protein kinase C zeta (PKCζ) levels in cord blood T cells (CBTC), associated with reduced ability to transition from a neonatal Th2 to a mature Th1 cytokine bias, leading to a higher risk of developing allergic sensitisation, compared to neonates whose T cells have ‘normal’ PKCζ levels. However, the importance of PKCζ signalling in regulating their differentiation from a Th2 to a Th1 cytokine phenotype propensity remains undefined. To define the role of PKCζ signalling in the regulation of CBTC differentiation from a Th2 to a Th1cytokine phenotype we have developed a neonatal T cell maturation model which enables the cells to develop to CD45RA−/CD45RO+ T cells while maintaining the Th2 immature cytokine bias, despite having normal levels of PKCζ. The immature cells were treated with phytohaemagglutinin, but in addition with phorbol 12‐myristate 13‐acetate (PMA), an agonist which does not activate PKCζ. This was compared to development in CBTC in which the cells were transfected to express constitutively active PKCζ. The lack of PKCζ activation by PMA was monitored by western blot for phospho‐PKCζ and translocation from cell cytosol to the membrane by confocal microscopy. The findings demonstrate that PMA fails to activate PKCζ in CBTC. The data show that CBTC matured under the influence of the PKC stimulator, PMA, maintain a Th2 cytokine bias, characterised by robust IL‐4 and minimal interferon gamma production (IFN‐γ), and lack of expression of transcriptional factor, T‐bet. This was also reflected in the production of a range of other Th2/Th1 cytokines. Interestingly, introduction of a constitutively active PKCζ mutant into CBTC promoted development towards a Th1 profile with high IFN‐γ production. The findings demonstrate that PKCζ signalling is essential for the immature neonatal T cells to transition from a Th2 to a Th1 cytokine production bias.

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Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells

Cited by 9 publications

References 40 publications

Putative Prevention of XML Injection Against Myocardial Ischemia Is Mediated by PKC and PLA2 Proteins

Putative Prevention of XML Injection Against Myocardial Ischemia Is Mediated by PKC and PLA2 Proteins

NRF2 Protects against Altered Pulmonary T Cell Differentiation in Neonates Following In Utero Ultrafine Particulate Matter Exposure

PKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN‐γ propensity

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