Human Stress Response Specificity through MAPK Bioresonance Selectivity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE289999 | GEO | 2025/03/04
REPOSITORIES: GEO
Similar Datasets
Project description:The mitogen-activated protein kinase (MAPK) p38 pathway is reported to regulate macrophage responses to lipopolysaccharide (LPS) at least partly via the phosphorylation of the mRNA-destabilizing factor tristetraprolin (TTP). LPS-activated MAPK p38 phosphorylates and activates the downstream kinase MAPK-activated protein kinase 2 (MK2), which then phosphorylates serines 52 and 178 of TTP, resulting in loss of mRNA-destabilizing activity. As a consequence, mRNAs that contain binding sites for TTP are stabilized in a manner that is acutely sensitive to the activity of the MAPK p38 pathway. Dual specificity phosphatase 1 (DUSP1) dephosphorylates and inactivates MAPK p38. Dusp1-/- macrophages overexpress a number of pro-inflammatory mediators, but their genome-wide responses to LPS have not yet been described in detail. Dusp1-/- mice are exceptionally sensitive to a wide variety of inflammatory challenges, including experimental models of endotoxemia or sepsis. It has been suggested (but not yet proven) that DUSP1 controls the inflammatory response of macrophages in part via the regulation of MAPK p38 activity and TTP phosphorylation status. We generated a mouse knock-in strain, in which codons 52 and 178 of the endogenous Zfp36 gene (which encodes TTP) were mutated to alanine codons. The mutation gives rise to a constitutively active form of TTP, which cannot be inactivated via the p38 MAPK pathway. The Zfp36aa/aa strain was back-crossed against C57/BL6 for > 10 generations. We also generated a double-targeted strain in which the Zfp36 mutation was combined with disruption of the Dusp1 gene. This expression array describes LPS responses of primary mouse bone marrow-derived macrophages of four genotypes, and closely matched genetic background: wild type (Dusp1+/+ : Zfp36+/+); TTP mutant (Zfp36aa/aa); DUSP1 knock out (Dusp1-/-); and double targeted (Dusp1-/- : Zfp36aa/aa). The data provide a comprehensive picture of the impact of Dusp1 deletion or TTP mutation on the responses of primary macrophages to LPS. They also demonstrate that the excessive inflammatory responses of Dusp1-/- macrophages are largely a consequence of the phosphorylation and inactivation of TTP. Genome wide expression profiles of wild type, Dusp1-/-, Zfp36aa/aa and Dusp1-/-/Zfp36aa/aa M-CSF derived macrophages, stimulated with LPS for 1 or 4 hours
2015-05-15 | E-GEOD-68449 | biostudies-arrayexpress
Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor
2013-05-31 | E-GEOD-40281 | biostudies-arrayexpress
Project description:The stress-activated p38 mitogen activated protein kinases (MAPK) mediate responses to osmotic shock, radiation, immune stimuli, inflammatory cues, and many other stresses. These kinases are activated rapidly, within seconds of stress induction, yet, their continuous activation, as commonly happens in inflammations and cancer, induce different signaling cascades than transient activation. This study aimed to follow the specific signaling cascades induced by two of these p38 MAPKs activated by strong and rapid stress, or by continuous (chronic) activations. The analysis was based on large-scale proteomics and phosphoproteomics analyses using SILAC labeling of mouse embryonic fibroblasts (MEF) deficient in each of these p38 kinases, expressing constitutively expressed wildtype p38α or p38β, or their intrinsically active variants. In addition, the effects of anisomycin, inducing strong and rapid stress response, were followed in wildtype MEF or in MEF knocked-out for these p38α or p38β. The signaling events, induced the each p38 during the chronic responses, indicated adaptations of the cells expressing the intrinsically active p38 mutants. The continuous activities of the individual p38 induced feedback loops that inactivated the other p38s. Furthermore, a number of new phosphorylation sites on proteins relevant to stress responses and cancer, such as p53 and p27, were revealed in this study.
2023-10-24 | PXD038389 | Pride
Project description:Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. We show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.
2023-04-26 | PXD033377 | Pride
Project description:The mitogen-activated protein kinase (MAPK) p38 pathway is reported to regulate macrophage responses to lipopolysaccharide (LPS) at least partly via the phosphorylation of the mRNA-destabilizing factor tristetraprolin (TTP). LPS-activated MAPK p38 phosphorylates and activates the downstream kinase MAPK-activated protein kinase 2 (MK2), which then phosphorylates serines 52 and 178 of TTP, resulting in loss of mRNA-destabilizing activity. As a consequence, mRNAs that contain binding sites for TTP are stabilized in a manner that is acutely sensitive to the activity of the MAPK p38 pathway. Dual specificity phosphatase 1 (DUSP1) dephosphorylates and inactivates MAPK p38. Dusp1-/- macrophages overexpress a number of pro-inflammatory mediators, but their genome-wide responses to LPS have not yet been described in detail. Dusp1-/- mice are exceptionally sensitive to a wide variety of inflammatory challenges, including experimental models of endotoxemia or sepsis. It has been suggested (but not yet proven) that DUSP1 controls the inflammatory response of macrophages in part via the regulation of MAPK p38 activity and TTP phosphorylation status. We generated a mouse knock-in strain, in which codons 52 and 178 of the endogenous Zfp36 gene (which encodes TTP) were mutated to alanine codons. The mutation gives rise to a constitutively active form of TTP, which cannot be inactivated via the p38 MAPK pathway. The Zfp36aa/aa strain was back-crossed against C57/BL6 for > 10 generations. We also generated a double-targeted strain in which the Zfp36 mutation was combined with disruption of the Dusp1 gene. This expression array describes LPS responses of primary mouse bone marrow-derived macrophages of four genotypes, and closely matched genetic background: wild type (Dusp1+/+ : Zfp36+/+); TTP mutant (Zfp36aa/aa); DUSP1 knock out (Dusp1-/-); and double targeted (Dusp1-/- : Zfp36aa/aa). The data provide a comprehensive picture of the impact of Dusp1 deletion or TTP mutation on the responses of primary macrophages to LPS. They also demonstrate that the excessive inflammatory responses of Dusp1-/- macrophages are largely a consequence of the phosphorylation and inactivation of TTP.
2015-05-15 | GSE68449 | GEO
Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression.
2013-05-31 | GSE40281 | GEO
Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Experiment Overall Design: Left ventricular gene expression profiles three days after MKK3bE + WT p38α gene transfer were compared with those of Lac Z âtreated animals by screening Affymetrix Rat Expression Set 230_2.0 Arrays (there are 5 samples in both group).
2009-04-25 | E-GEOD-3866 | biostudies-arrayexpress
Project description:Differentiation therapy with all-trans retinoic acid (ATRA) is well established for acute promyelocytic leukemia (APL). However, the narrow application and tolerance development of ATRA remain to be improved. A number of kinase inhibitors have been reported to induce differentiation. In this study, we challenged several combinations of these kinase inhibitors. As a result, we found that the combination of Akt inhibitor Triciribine (TCN) and several p38 MAPK inhibitors have profound effect for differentiation in several myeloid cell lines. To reveal the molecular mechanisms involved in TCN and p38 MAPK inhibitor induced differentiation, we performed microarray analysis.
2023-06-27 | GSE235632 | GEO
Project description:Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.
2022-03-03 | MTBLS2436 | MetaboLights
Project description:Analysis of the p38 MAPK pathway in regulation of dendritic cells (DCs) differentiation at the gene expression level. Bone marrow cells were cultured with mGM-CSF (20 ng/ml) in the presence of 1.5 mM of SB202190 or 0.1% DMSO. At day 7, semi-adherent cells were collected as immature DCs (iDCs). iDCs were matured by TNF-a (10 ng/ml) and IL-1b (10 ng/ml) for 48 hours. Results showed that p38 MAPK activity in DC progenitor cells acts as an antigen presentation attenuator, and disabling this critical brake during DC differentiation endows DCs with enhanced immunogenicity, which may be useful for the induction of antitumor immune responses. Total RNA was obtained from 2-day-cultured bone marrow cells, iDCs and mature DCs.
2014-05-22 | E-GEOD-57879 | biostudies-arrayexpress