scholarly journals MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18

2010 ◽  
Vol 207 (8) ◽  
pp. 1625-1636 ◽  
Author(s):  
Rosalba Salcedo ◽  
Andrea Worschech ◽  
Marco Cardone ◽  
Yava Jones ◽  
Zsofia Gyulai ◽  
...  
Keyword(s):  
Differential Susceptibility ◽  
Adaptor Protein ◽  
Protective Role ◽  
Dss Colitis ◽  
Expression Of Genes ◽  
Cancer Models ◽  
Genes Encoding ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor ◽  
Deficient Mice

Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88−/− mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the β-catenin gene. Others have reported that toll-like receptor (Tlr) 4–deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18−/− and Il18r1−/− mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88−/− mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.

scholarly journals A MyD88-Deficient Mouse Model Reveals a Role for Nramp1 in Campylobacter jejuni Infection

2007 ◽  
Vol 75 (4) ◽  
pp. 1994-2003 ◽  
Author(s):  
Robert O. Watson ◽  
Veronica Novik ◽  
Dirk Hofreuter ◽  
María Lara-Tejero ◽  
Jorge E. Galán
Keyword(s):  
Campylobacter Jejuni ◽  
Virulence Genes ◽  
Potential Role ◽  
Bacterial Pathogen ◽  
Adaptor Protein ◽  
Myeloid Differentiation ◽  
Deficient Mouse ◽  
Immunocompetent Mice ◽  
Myeloid Differentiation Factor ◽  
Deficient Mice

ABSTRACT Campylobacter jejuni is a major worldwide cause of enteric illnesses. Adult immunocompetent mice are not susceptible to C. jejuni infection. However, we show here that mice deficient in the adaptor protein myeloid differentiation factor 88 (MyD88), which is required for signaling through most Toll-like receptors, can be stably colonized by C. jejuni but not by isogenic derivatives carrying mutations in known virulence genes. We also found that Nramp1 deficiency increases the mouse susceptibility to C. jejuni infection when administered systemically. These results indicate that MyD88-deficient mice could be a useful model to study C. jejuni colonization and reveal a potential role for Nramp1 in the control of this bacterial pathogen.

scholarly journals Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenliang Su ◽  
Huan Cui ◽  
Danning Wu ◽  
Jiawen Yu ◽  
Lulu Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Mobility ◽  
Adaptor Protein ◽  
Immunofluorescent Staining ◽  
Inhibitory Peptide ◽  
Tlr4 Signaling ◽  
Innate Immunity Pathway ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

Abstract Background As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure. Methods The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain. Results Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH. Conclusions HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.

scholarly journals Olfactory learning primes the heat shock transcription factor HSF-1 to enhance the expression of molecular chaperone genes in C. elegans

2017 ◽  
Author(s):  
Felicia K. Ooi ◽  
Veena Prahlad
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Molecular Chaperone ◽  
Pathogenic Bacteria ◽  
Environmental Enrichment ◽  
Protective Role ◽  
C Elegans ◽  
Expression Of Genes ◽  
Genes Encoding

AbstractLearning, a process by which animals modify their behavior as a result of experience, allows organisms to synthesize information from their surroundings to acquire resources and predict danger. Here we show that prior encounter with the odor of pathogenic bacteria prepares Caenorhabditis elegans to survive actual exposure to the pathogen by increasing HSF-1-dependent expression of genes encoding molecular chaperones. Learning-mediated enhancement of chaperone gene expression requires serotonin. Serotonin primes HSF-1 to enhance the expression of molecular chaperone genes by promoting its localization to RNA polymerase II–enriched nuclear loci, even prior to transcription. HSF-1-dependent chaperone gene expression ensues, however, only if and when animals encounter the pathogen. Thus, learning equips C. elegans to better survive environmental dangers by pre-emptively and specifically initiating transcriptional mechanisms throughout the whole organism. These studies provide one plausible basis for the protective role of environmental enrichment in disease.

scholarly journals Post-Effort Changes in Autophagy- and Inflammation-Related Gene Expression in White Blood Cells of Healthy Young Men

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1406
Author(s):  
Dorota Kostrzewa-Nowak ◽  
Alicja Trzeciak-Ryczek ◽  
Paweł Wityk ◽  
Danuta Cembrowska-Lech ◽  
Robert Nowak
Keyword(s):  
White Blood Cells ◽  
Physical Exertion ◽  
Protective Role ◽  
Metabolic Disturbances ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Genes Encoding ◽  
Ifn Γ ◽  
Bioenergetic Cost

Acute, strenuous physical exertion requiring high levels of energy production induces the production of reactive oxygen species and metabolic disturbances that can damage the mitochondria. Thus, selective autophagic elimination of defective mitochondria may improve resistance to oxidative stress and potentially to inflammation. The main goal of this study was to evaluate the impacts of intense effort on changes in the expression of select genes related to post-effort inflammation and autophagy. Thirty-five men aged 16–21 years were recruited to the study. The impacts of both aerobic (endurance) and anaerobic (speed) efforts on selected genes encoding chemokines (CXCL5, 8–12) were analyzed. Significant increases in the expression of all studied genes excluding CXCL12 were observed. Moreover, both types of effort induced an increase in the expression of genes encoding IL-2, -4, -6, -10, IFN-γ and TNF-α, excluding IL-17A. Generally, these efforts caused a significant increase in the relative expression of apoptosis- (BCL2 and BAX) and autophagy- (BNIP3, BECN1, MAP1LC3B, ATG5, ATG7, ATG12, ATG16L1 and SQSTM1) related genes. It seems that the duration of physical activity and its bioenergetic cost has an important impact on the degree of increase in expression of this panel of autophagy-related genes. Anaerobic effort is more strenuous than aerobic effort and requires a higher bioenergetic investment. This may explain the stronger impact of anaerobic effort on the expression of the studied genes. This observation seems to support the protective role of autophagy proposed in prior studies.

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