scholarly journals Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

2014 ◽  
Vol 192 (4) ◽  
pp. 1855-1861 ◽  
Author(s):  
Yetao Wang ◽  
Lei Hu ◽  
Xiaomei Tong ◽  
Xin Ye
Keyword(s):  
Signaling Pathway ◽  
Casein Kinase ◽  
Tlr Signaling ◽  
Tlr Signaling Pathway

scholarly journals MicroRNA-34a Inhibition of the TLR Signaling Pathway Via CXCL10 Suppresses Breast Cancer Cell Invasion and Migration

2018 ◽  
Vol 46 (3) ◽  
pp. 1286-1304 ◽  
Author(s):  
Min Xu ◽  
Dong Li ◽  
Chen Yang ◽  
Jian-Song Ji
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Breast Tumorigenesis ◽  
Tlr Signaling ◽  
T47d Cells ◽  
Tlr Signaling Pathway ◽  
Mcf 7

Background/Aims: Breast cancer (BC) starts as a local disease, but it can metastasize to the lymph nodes and distant organs. However, the metastatic process is still poorly understood. The mRNA microarray datasets GSE26910 and GSE33447 show that CXCL10 is up-regulated in BC, and the microRNA microarray dataset GSE38167 and a network meta-analysis of microRNA expression profile studies in human BC suggest that microRNA-34a (miR-34a) is down-regulated in BC. CXCL10 was predicted as a target of miR-34a by microRNA.org. In this study, we uncovered a CXCL10-independent mechanism by which miR-34a exerts its antimetastatic activity in BC. Methods: To investigate the clinical significance of miR-34a in BC, we collected cancer tissues and paracancerous tissues from 258 patients with BC. In addition, a series of inhibitors, mimics, and siRNAs was introduced into MCF-7 and T47D cells to validate the regulatory mechanisms by which miR-34a regulates CXCL10. Next, to better understand the pivotal role of TLR signaling pathway inhibition in MCF-7 and T47D cells, we blocked the TLR signaling pathway using OxPAPC, an antagonist of TLR signaling. Results: Among BC patients, miR-34a was down-regulated, CXCL10 was up-regulated, and the TLR signaling pathway was activated. Determination of luciferase activity revealed that CXCL10 was a target of miR-34a. Through gain- and loss-of-function studies, miR-34a was demonstrated to negatively regulate CXCL10; inhibit activation of the TLR signaling pathway; significantly suppress in vitro cell proliferation, migration, and invasion; and induce apoptosis. Conclusion: Our findings suggest that functional loss or suppression of the tumor suppressor CXCL10 due to induction of miR-34a leads to inhibition of the TLR signaling pathway during breast tumorigenesis, providing a novel target for the molecular treatment of breast malignancies.

scholarly journals NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages

2020 ◽  
Vol 295 (18) ◽  
pp. 6236-6248
Author(s):  
Frank Fang-Yao Lee ◽  
Kevin Davidson ◽  
Chelsea Harris ◽  
Jazalle McClendon ◽  
William J. Janssen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Chronic Inflammation ◽  
Mrna Splicing ◽  
Dominant Negative ◽  
Mrna Isoforms ◽  
Inflammatory Signaling ◽  
Tlr Signaling ◽  
Tlr4 Agonist ◽  
Alternatively Spliced ◽  
Tlr Signaling Pathway

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

scholarly journals Functional Toll-Like Receptors (TLRs) Are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway Is Associated with a More Favorable Phenotype

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 973 ◽  
Author(s):  
Annette K. Brenner ◽  
Øystein Bruserud
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathway ◽  
Myeloid Leukemia ◽  
Receptor Expression ◽  
Cytokine Secretion ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
General Response ◽  
Tlr Signaling Pathway ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a highly heterogeneous disease with regard to biological characteristics and receptor expression. Toll-like receptors (TLRs) are upstream to the transcription factor NFκB and part of the innate immune system. They are differentially expressed on AML blasts, and during normal hematopoiesis they initiate myeloid differentiation. In this study, we investigated the response upon TLR stimulation in an AML cohort (n = 83) by measuring the increase of NFκB-mediated cytokine secretion. We observed that TLR4 is readily induced in most patients, while TLR1/2 response was more restricted. General response to TLR stimulation correlated with presence of nucleophosmin gene mutations, increased mRNA expression of proteins, which are part of the TLR signaling pathway and reduced expression of transcription-related proteins. Furthermore, signaling via TLR1/2 appeared to be linked with prolonged patient survival. In conclusion, response upon TLR stimulation, and especially TLR1/2 induction, seems to be part of a more favorable phenotype, which also is characterized by higher basal cytokine secretion and a more mature blast population.

scholarly journals The Effects of Paclitaxel and Metformin and Combined Treatments on TLR Signaling Pathway on MDA-MB-231 Breast Cancer Cell Lines

Proceedings ◽  
2017 ◽  
Vol 1 (10) ◽  
pp. 1016 ◽  
Author(s):  
Melike Ozgul ◽  
Elgin Turkoz Uluer ◽  
Tuna Onal ◽  
Damla Akogullari ◽  
Kemal Ozbilgin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Combined Treatments ◽  
Tlr Signaling ◽  
Tlr Signaling Pathway

Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 28-28 ◽  
Author(s):  
Lori A Kelly ◽  
Ali H Zaidi ◽  
Mark Barlek ◽  
Rachael Kreft ◽  
Ashten Omstead ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Direct Proof ◽  
Acid Reflux ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Molecular Sequence ◽  
E Coli ◽  
Post Surgery ◽  
Tlr Signaling Pathway

28 Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.

scholarly journals Hepatitis C Virus Nonstructural Protein 5A Modulates the Toll-Like Receptor-MyD88-Dependent Signaling Pathway in Macrophage Cell Lines

2007 ◽  
Vol 81 (17) ◽  
pp. 8953-8966 ◽  
Author(s):  
Takayuki Abe ◽  
Yuuki Kaname ◽  
Itsuki Hamamoto ◽  
Yoshimi Tsuda ◽  
Xiaoyu Wen ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Immune Cells ◽  
Cytokine Production ◽  
Toll Like Receptor ◽  
Macrophage Cell ◽  
Tlr Signaling ◽  
Tlr Signaling Pathway

ABSTRACT Hepatitis C virus (HCV) infection induces a wide range of chronic liver injuries; however, the mechanism through which HCV evades the immune surveillance system remains obscure. Blood dendritic cells (DCs) play a pivotal role in the recognition of viral infection and the induction of innate and adaptive immune responses. Several reports suggest that HCV infection induces the dysfunction of DCs in patients with chronic hepatitis C. Toll-like receptor (TLR) has been shown to play various roles in many viral infections; however, the involvement of HCV proteins in the TLR signaling pathway has not yet been precisely elucidated. In this study, we established mouse macrophage cell lines stably expressing HCV proteins and determined the effect of HCV proteins on the TLR signaling pathways. Immune cells expressing NS3, NS3/4A, NS4B, or NS5A were found to inhibit the activation of the TLR2, TLR4, TLR7, and TLR9 signaling pathways. Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. Amino acid residues 240 to 280, previously identified as the interferon sensitivity-determining region (ISDR) in NS5A, interacted with the death domain of MyD88, and the expression of a mutant NS5A lacking the ISDR partially restored cytokine production. These results suggest that the expression of HCV proteins modulates the TLR signaling pathway in immune cells.

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