CGMP signaling pathway that modulates NF-κB activation in innate immune responses.
Ontology highlight
ABSTRACT:
SUBMITTER: Kanoh H
PROVIDER: S-EPMC8710550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The C-type lectin receptors (CLRs) belong to a large family of proteins that contain a carbohydrate recognition domain (CRD) and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors (PRRs) recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs (ITAMs) or interacting with ITAM-containing adaptor proteins such as FcRγ. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB (NF-κB) family of transcriptional factors through a Syk- and CARD9-dependent pathway(s). The activation of NF-κB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs, and how these CLRs activate NF-κB and contribute to innate immune and inflammatory responses.
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Project description:Quercetin, the main component of flavonoids, has a wide range of biological actions. Quercetin can be made into a variety of additives for practice, because of the stable chemical structure and water-soluble derivatives. This study was intended to explore the effects of quercetin on immune function and its regulatory mechanism in Arbor Acre broiler to provide a practical basis for improving poultry immune function and figure out the optimum supplementation as functional feed additives. A total of 240 one-day-old healthy Arbor Acre broilers, similar in body weight, were randomly allotted to 4 treatments with 6 replicates, 10 broilers in each replicate and fed with diets containing quercetin at 0, 0.02, 0.04, and 0.06% for 6 wk. Blood and immune organs (spleen, thymus, and bursa) were collected from chickens at the end of the experiment. Growth performance, immune organs indexes, contents of serum immune molecules, splenic T lymphocyte proliferative responses, and expression of immune related genes were evaluated. The results showed that dietary quercetin had no significant effect (P > 0.05) on growth performance of broilers. Compared with control, 0.06% quercetin supplementation in diet significantly increased spleen index and thymus index (P < 0.05). It also increased the secretion of immune molecules including immunoglobulin A (IgA), interleukin-4 (IL-4) (P < 0.001), immunoglobulin M (IgM) (P = 0.007), complement component 4 (C4) (P = 0.001), and tumor necrosis factor-α (TNF-α) (P < 0.05). On the other hand, 0.02% quercetin supplementation significantly increased complement component 3 (C3) (P < 0.05). Additionally, both 0.04 and 0.06% quercetin supplementation significantly increased expression of TNF-α, TNF receptor associated factor-2 (TRAF-2), TNF receptor superfamily member 1B (TNFRSF1B), nuclear factor kappa-B p65 subunit (NF-κBp65), and interferon-γ (IFN-γ) mRNA (P < 0.05), and expression of NF-κB inhibitor-alpha (IκB-α) mRNA were significantly decreased (P < 0.05). Thus, quercetin improved immune function via NF-κB signaling pathway triggered by TNF-α.
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Project description:Background: The most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), has a worse prognosis and a higher probability of relapse since there is a narrow range of treatment options. Identifying and testing potential therapeutic targets for the treatment of TNBC is of high priority. Methods: Using a transcriptional signature of triple-negative breast cancer collected from Gene Expression Omnibus (GEO), CMap was utilized to reposition compounds for the treatment of TNBC. CCK8 and colony formation experiments were performed to detect the effect of the candidate drug on the proliferation of TNBC cells, while flow cytometry was used to detect cell apoptosis. Meanwhile, transwell assay was implemented to detect cell metastasis change caused by the candidate drug. Moreover, the proteomic approach was presently ongoing to evaluate the underlying mechanism of the candidate drug in TNBC. Furthermore, drug affinity responsive target stability (DARTS) coupled with LC-MS/MS was carried out to explore the potential drug target candidate in TNBC cells. Results: We found that the most widely used medication, eugenol, reduced the growth and metastasis of TNBC cells. According to the underlying mechanism revealed by proteomics, eugenol could inhibit TNBC cell proliferation via the NOD1-NF-κB signaling pathway. DARTS experiment further revealed that eugenol may bind to NF-κB in TNBC cells. Concludes: Our findings pointed out that eugenol was a potential candidate drug for the treatment of TNBC.
2023-05-10 | PXD039305 | Pride
Project description:Endothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases; however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-κB signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-α, IL-1β, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-α in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-α stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of IκBα and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14-NF-κB forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.
| S-EPMC7181718 | biostudies-literature
Project description:The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.
| S-EPMC3193406 | biostudies-other
Project description:Background: In contrast to HIV-1, lentiviruses of the HIV-2/SIVmac/SIVsmm lineage are capable of efficient replication in myeloid cells due to the presence of their accessory protein Vpx. Vpx has been shown to induce degradation of the dNTP triphosphohydrolase SAMHD1, which is a cellular restriction factor of lentiviral replication. Furthermore, Vpx is important for nuclear import of the viral pre-integration complex. To identify further functions of Vpx, we have analyzed the effect of Vpx on cellular gene expression in monocytes. Therefore, we performed whole genome microarray analysis of unstimulated primary human monocytes treated with SIV–based virus-like particles containing Vpx (VLP+Vpx) or lacking Vpx (VLP). Results: Comparison of the gene expression profiles of human monocytes treated with VLP+Vpx and VLP revealed that Vpx down-regulates various genes involved in innate immunity, in particular genes that are known to be regulated by the transcription factor NF-κB. Subsequent analysis of p65 nuclear translocation revealed that Vpx inhibits the VLP-induced activation of NF-κB. Counteraction of NF-κB was also obtained using Vpx mutants lacking the capacity to induce SAMHD1 degradation. Conclusions: Independent of its capacity to induce degradation of SAMHD1, Vpx is involved in regulation of cellular gene expression. In particular, Vpx is able to modulate innate immune responses through down-regulation of TLR-induced NF-κB activation. This points to a significant role of Vpx in the pathogenicity of SIV, as the lower pathogenicity of SIV compared to HIV-1 has been associated to lower innate immunity responses.
2014-06-28 | GSE48542 | GEO
Project description:OBJECTIVE:We focused on the effects of PTGS2/NF-κB signaling pathway on the radiation resistance of glioma in the study. METHODS:We downloaded the microarray data from the Gene Expression Omnibus (GEO) database. We verified transfection successfully through QRT-PCR analysis. Immunofluorescence was used to detect γH2AX content under 2 Gy radiation. The survival rates of cells under 2 Gy irradiation were tested by clonogenic survival assay. Flow cytometry was used to detect cell cycle. Western blot was applied to detect the expression of NF-κB pathway-related proteins. We also used MTT assay to detect the proliferation of cells. RESULTS:In this research, we discovered that the expression of the PTGS2 was upregulated in radiation-resistant glioma cells. The radio-tolerance rate of U87 cells was obviously elevated after the overexpression of PTGS2. The radioresistance of U87R cells was significantly reduced after the knockdown of PTGS2. After radiotherapy, the number of cells arrested in G2/M phase decreased after PTGS2 overexpression in U87cells but increased in PTGS2 knockdown in U87R cells. The survival rate of U87 and U87R cells under radiation decreased significantly after the addition of NF-κB inhibitor. The proliferation of U87 cells was suppressed by radiation and the addition of Bay 11. In addition, PTGS2 activated NF-κB signaling pathway and prevented DNA damage after radiotherapy. Lastly, PTGS2 was proved to facilitate tumor cell proliferation and improve the radio-tolerance. CONCLUSION:PTGS2/NF-κB signaling pathway was involved in radio-tolerance of glioma cells, which provided a new insight into glioma therapy.
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Project description::Mycobacterium tuberculosis is considered a successful pathogen with multiple strategies to undermine host immunity. The YrbE3A is encoded by Rv1964 within the RD15 region present in the genome of Mtb, but missing in M.bovis, M.bovis BCG (Pasteur) strain, and M. smegmatis (Ms). However, little is known about its function. In this study, the YrbE3A gene was cloned into pMV261 and expressed in Ms and BCG, while the strains with the vector served as the controls. The YrbE3A was expressed on the mycobacterial membrane, and the purified protein could stimulate RAW264.7 cells to produce IL-6. Furthermore, the effect of the recombinant strains on cytokine secretion by RAW264.7 was confirmed, which varied with the host strains. Ms_YrbE3A increased significantly higher levels of TNF-α and IL-6 than did Ms_vec, while BCG_YrbE3A enhanced higher TNF-α than BCG_vec. The pathways associated with NF-κB p65 and MAPK p38/JNK, other than Erk1/2, regulated this process. In addition, mice were infected with Ms_YrbE3A and Ms-vec and were kinetically examined. Compared to Ms-vec, Ms_YrbE3A induced more serious inflammatory damage, higher levels of TNF-α and IL-6, higher numbers of lymphocytes, neutrophils, and monocytes in a time-dependent way, but lower lung bacterial load in lung. These findings may contribute to a better understanding of Mtb pathogenesis.
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Project description:Influenza A virus (IAV), a highly infectious respiratory pathogen, remains a major threat to global public health. Numerous long non-coding RNAs (lncRNAs) have been shown to be implicated in various cellular processes. Here, we identified a new lncRNA termed RIG-I-dependent IAV-upregulated noncoding RNA (RDUR), which was induced by infections with IAV and several other viruses. Both in vitro and in vivo studies revealed that robust expression of host RDUR induced by IAV was dependent on the RIG-I/NF-κB pathway. Overexpression of RDUR suppressed IAV replication and downregulation of RDUR promoted the virus replication. Deficiency of mouse RDUR increased virus production in lungs, body weight loss, acute organ damage and consequently reduced survival rates of mice, in response to IAV infection. RDUR impaired the viral replication by upregulating the expression of several vital antiviral molecules including interferons (IFNs) and interferon-stimulated genes (ISGs). Further study showed that RDUR interacted with ILF2 and ILF3 that were required for the efficient expression of some ISGs such as IFITM3 and MX1. On the other hand, we found that while NF-κB positively regulated the expression of RDUR, increased expression of RDUR, in turn, inactivated NF-κB through a negative feedback mechanism to suppress excessive inflammatory response to viral infection. Together, the results demonstrate that RDUR is an important lncRNA acting as a critical regulator of innate immunity against the viral infection.
| S-EPMC8160526 | biostudies-literature
Project description:NOD-like receptors (NLRs) play a large role in regulation of host innate immunity, yet their role in periodontitis remains to be defined. NLRX1, a member of the NLR family that localizes to mitochondria, enhances mitochondrial ROS (mROS) generation. mROS can activate the NLRP3 inflammasome, yet the role of NLRX1 in NLRP3 inflammasome activation has not been examined. In this study, we revealed the mechanism by which NLRX1 positively regulates ATP-induced NLRP3 inflammasome activation through mROS in gingival epithelial cells (GECs). We found that depletion of NLRX1 by shRNA attenuated ATP-induced mROS generation and redistribution of the NLRP3 inflammasome adaptor protein, ASC. Furthermore, depletion of NLRX1 inhibited Fusobacterium nucleatum infection-activated caspase-1, suggesting that it also inhibits the NLRP3 inflammasome. Conversely, NLRX1 also acted as a negative regulator of NF-κB signaling and IL-8 expression. Thus, NLRX1 stimulates detection of the pathogen F. nucleatum via the inflammasome, while dampening cytokine production. We expect that commensals should not activate the inflammasome, and NLRX1 should decrease their ability to stimulate expression of pro-inflammatory cytokines such as IL-8. Therefore, NLRX1 may act as a potential switch with regards to anti-microbial responses in healthy or diseased states in the oral cavity.
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