TRPV4 activation induces TMJ degeneration via p38 MAPK/c-Fos/CXCLs axis
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PROVIDER: PRJNA1180614 | ENA |
REPOSITORIES: ENA
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Project description:Degenerative joint disease mainly manifests abnormal bone and cartilage remodeling, articular disc deformation and synovial inflammation, and it is closely related to intraarticular overload. Activation of the mechanosensitive channel transient receptor potential vanilloid 4 (TRPV4) can lead to degeneration of the temporomandibular joint (TMJ) disc. However, the potential mechanism by which TRPV4 leads to TMJ degeneration are still unclear. The results showed that TRPV4 activation promoted upregulation of chemokines including CXCL6 and CXCL13 in disc cells, and such chemokine release facilitated the proliferation and migration of FLSs and aggravated the TMJ degeneration in rat. Mechanistically, TRPV4-induced p38 MAPK signaling pathway activation promoted chemokine expression via the nuclear translocation of p38 and c-Fos, thereby promoting the proliferation and migration by CXCL-CXCR interaction.
2024-11-07 | GSE280821 | 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. Keywords: Gene transfer
2006-12-19 | GSE3866 | GEO
Project description:Abstract Background Chronic constipation is prevalent and involves both colon sensitivity and various changes in intestinal bacteria, particularly mucosa-associated microflora. Here we examined regulatory mechanisms of TRPV4 expression by co-culturing colon epithelial cell lines with intestinal bacteria and their derivatives. We also investigated TRPV4 expression in colon epithelium from patients with constipation. Methods Colon epithelial cell lines were co-cultured with various enterobacteria (bacterial components and supernatant), folate, LPS, or short chain fatty acids (SCFAs). TRPV4 expression levels and promoter DNA methylation were assessed using pyrosequencing, and microarray network analysis. For human samples, correlation coefficients were calculated and multiple regression analyses were used to examine the association between clinical background, rectal TRPV4 expression level and mucosa-associated microbiota. Results Co-culture of CCD841 cells with P. acnes, C. perfringens, or S. aureus transiently decreased TRPV4 expression but did not induce methylation. Co-culture with clinical isolates and standard strains of K. oxytoca, E. faecalis, or E. coli increased TRPV4 expression in CCD841 cells, and TRPV4 and TNF-alpha expression were increased by E. coli culture supernatants but not bacterial components. Although folate, LPS, IL-6, TNF-alpha, or SCFAs alone did not alter TRPV4 expression, TRPV4 expression following exposure to E. coli culture supernatants was inhibited by butyric acid or TNF-alphaR1 inhibitor and increased by p38 inhibitor. Microarray network analysis showed activation of TNF-alpha, cytokines, and NOD signaling. TRPV4 expression was higher in constipated patients from the terminal ileum to the colorectum, and multiple regression analyses showed that low stool frequency, frequency of defecation aids, and duration were associated with TRPV4 expression. Meanwhile, incomplete defecation, time required to defecate, and number of defecation failures per 24 hours were associated with increased E. faecalis frequency. Conclusions Colon epithelium cells had increased TRPV4 expression upon co-culture with K. oxytoca, E. faecalis, or E. coli supernatants, as well as TNFα-stimulated TNFαR1 expression via a pathway other than p38. Butyrate treatment suppressed this increase. Epithelial TRPV4 expression was increased in constipated patients, suggesting that TRPV4 together with increased frequency of E. faecalis may be involved in the pathogenesis of various constipation symptoms.
2022-07-15 | GSE208164 | GEO
Project description:SARS-CoV-2, the causative agent of the COVID-19 pandemic, drastically modifies the cells that it infects. One such effect is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammation pathways that are dysregulated in severe COVID-19 cases. Inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduces both cytokine production and viral replication. Here, we applied a systems biology approach to better understand interactions between the p38/MAPK pathway and SARS-CoV-2 in human lung epithelial cells. We found several components of the p38/MAPK pathway positively and negatively impact SARS-CoV-2 infection and that p38ß is a required host factor for SARS-CoV-2 that acts by promoting viral protein translation in a manner that prevents innate immune sensing. Furthermore, we combined chemical and genetic perturbations of p38ß with quantitative phosphoproteomics to identify novel, putative p38ß substrates in an unbiased manner, with broad relevance beyond SARS-CoV-2 biology.
2022-01-21 | GSE183999 | GEO
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38M-NM-1 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38M-NM-1 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS WT vs. p38alphaCKO macrophages, male vs. female
2013-10-29 | E-GEOD-51707 | biostudies-arrayexpress
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
Project description:The transcription factor EB (TFEB) regulates energy homeostasis and cellular response to a wide variety of stress conditions, including nutrient deprivation, oxidative stress, organelle damage, and pathogens. Here we identify S401 as a novel phosphorylation site within the TFEB proline-rich domain. Phosphorylation of S401 increases significantly in response to oxidative stress, UVC light, growth factors and LPS, whereas this increase is prevented by p38 MAPK inhibition or depletion, revealing a new role for p38 MAPK in TFEB regulation. Mutation of S401 in THP1 cells demonstrates that the p38 MAPK/TFEB pathway plays a particularly relevant role during monocyte differentiation into macrophages. TFEB-S401A monocytes fail to upregulate expression of multiple immune genes in response to PMA-induced differentiation, including critical cytokines, chemokines, and growth factors. Polarization of M0 macrophages into M1 inflammatory macrophages is also aberrant in TFEB-S401A cells. These results indicate that TFEB-S401 phosphorylation links differentiation signals to the transcriptional control of monocyte differentiation.
2022-12-06 | GSE217608 | GEO
Project description:p38-MAPKs are stress activated kinases necessary for placental development and nutrient and oxygen transfer during murine post-implantation development. In preimplantation development, p38-MAPK activity is required for blastocyst formation. Additionally, we have previously reported its role in regulating specification of inner cell mass (ICM) towards primitive endoderm (PrE), although a comprehensive mechanistic understanding is currently limited. Adopting live embryo imaging, proteomic and transcriptomic approaches, we report experimental data that directly address this deficit. Chemical inhibition of p38-MAPK activity during blastocyst maturation causes impaired blastocyst cavity expansion, most evident between the third and tenth hours post inhibition onset. We identify an overlapping minimal early blastocyst maturation window of p38-MAPKi inhibition (p38-MAPKi) sensitivity, that is sufficient to impair PrE cell fate by the late blastocyst (E4.5) stage. Comparative proteomic analyses reveal substantial downregulation of ribosomal proteins, the mRNA transcripts of which are also significantly upregulated. Ontological analysis of the differentially expressed transcriptome during this developmental period reveals “translation” related gene transcripts as being most significantly, yet transiently, affected by p38-MAPKi. Moreover, combined assays consistently report concomitant reductions in de novo translation that are associated with accumulation of unprocessed rRNA precursors. Using a phospho-proteomic approach, ± p38-MAPKi, to potentially identify p38-MAPK effectors, we report that clonal siRNA mediated knockdown of Mybpp1a, an rRNA transcription and processing regulator gene, is associated with significantly diminished PrE contribution. Lastly, we show that defective PrE specification caused by p38-MAPKi (but not MEK/ERK signalling inhibition) can be partially rescued by activating the archetypal mTOR mediated translation regulatory pathway. Activated p38-MAPK controls blastocyst maturation in an early and distinctly transient developmental window by regulating gene functionalities related to translation, that creates a permissive environment for appropriate specification of ICM cell fate.
2021-06-28 | PXD025711 | Pride
Project description:Lung cancer is the main cause of cancer-related death in men and women all over the world. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, with the overall 5-year survival rate is less than 20% . We found the mRNA expression of c-Fos in LUAD clinical samples was decreased significantly compared to adjacent normal control. Overexpression of c-Fos inhibited LUAD cell proliferation, colony formation, and induced cell apoptosis while c-Fos knockdown promoted cell proliferation, colony formation, and suppressed cell apoptosis. Cell cycle showed little difference after c-Fos knockdown but overexpression of c-Fos increased the distribution of G1 phase when decreased G2 phase cells. Knockdown of c-Fos reduced the sensitivity of LUAD cells to cisplatin but overexpression of c-Fos increased the efficacy of cisplatin both in vitro and in vivo. MAPK signaling pathway was enriched after c-Fos was overexpressed in LUAD cells. The expression of c-Jun, c-Myc and DUSP1 was greatly inhibited after c-Fos overexpression but incresed after c-Fos knockdown, which suggests c-Fos regulated MAPK signaling pathway in LUAD. Furthermore, c-Fos was shown to interact with c-Jun and overexpression of c-Jun partially recovered the expression of c-Jun, c-Myc and DUSP1 caused by c-Fos overexpression. Cell proliferation was also rescued when apoptosis was decreased followed by c-Jun overexpression. In contrast, knockdown of c-Jun inhibited cell proliferation and promoted cell apoptosis in LUAD cells when reduced the level of c-Jun, c-Myc and DUSP1. In summary, c-Fos inhibits cell proliferation, promotes apoptosis and increses cisplatin-sensitivity of lung adenocarcinoma cells via regulating MAPK signaling by interacting with c-Jun in certain LUADs.
2023-09-20 | GSE213590 | GEO
Project description:Muscleblind Splicing Factor Regulates Longevity Through p38 MAPK Signaling
| PRJNA611999 | ENA