Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis

Yang, Cheng; Zhu, Yun; Huang, Xiuping; Zhang, Wei; Han, Zelong; Liu, Side

doi:10.1371/journal.pone.0126803

Cited by 44 publications

(43 citation statements)

References 58 publications

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“…Similarly, previous results have concluded that TLR2 (either TLR2/1 or TLR2/6) and TLR4 activation decrease significantly 5-HT uptake in Caco-2/TC7 cells [21,22]. Moreover, the over-expression of both receptors has been implicated in IBD [14]. Accordingly, we have analyzed the possible interaction between TLR2 and TLR4 with NOD2.…”

Section: Interdependence Among Tlr2 Tlr4 and Nod2 In Caco-2/tc7 Cellssupporting

confidence: 59%

“…PRRs are expressed in intestinal epithelial cells [11,12] and are able to recognize microbial-associated molecular patterns (MAMPs) to develop either inflammatory or tolerance responses [13]. In this context, several studies have reported that numerous PRRs, as TLR2, TLR4 [14] and NOD2 [15], seem to be implicated in IBD due to the dysfunctional recognition of commensal microbiota [16]. TLR2 is expressed in the cell surface and can detect molecular patterns associated with Gram-positive bacteria [17] through their heterodimers (TLR2/1 and TLR2/6) [18] while TLR4, also located on the cell surface, detects lipopolysaccharide (LPS), the major cell wall component of Gramnegative bacteria [19].…”

Section: Introductionmentioning

confidence: 99%

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NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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Section: Interdependence Among Tlr2 Tlr4 and Nod2 In Caco-2/tc7 Cellssupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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“…Persons with this TLR4 haplotype are less responsive to LPS and have an increased risk of severe infection by gram-negative bacteria (22), as well as of chronic inflammatory bowel disease (23). rs4986790 may protect against malaria (24), yet increases the global cancer risk (25).…”

Section: Loss-of-function Polymorphism In Tlr4mentioning

confidence: 99%

“…It is noteworthy that the common variants in TLR3 and TLR4 that worsen the prognosis of breast cancer patients also affect the susceptibility to a variety of infectious disease. As a possibility, human populations who are heterogeneous in the function of these PRRs might have the evolutionary advantage that portions of them are protected against lethal or chronic infection by specific microorganisms (22)(23)(24), explaining why SNPs affecting major PRRs have been maintained over evolution. To our knowledge, no study has linked rs867228 in FPR1 to a particular disease.…”

Section: Implications and Future Directionsmentioning

confidence: 99%

Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy

et al. 2016

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Pattern recognition receptors allow the innate immune system to perceive the presence of microbial products and to launch the first steps of the defense response. Some pattern recognition receptors also sense endogenous ligands that are released from uninfected dying cells, thereby activating immune responses against dead-cell antigens. This applies to toll-like receptors 3 and 4 (TLR3, TLR4), which sense doublestranded RNA and high-mobility group protein B1 (HMGB1), respectively, as well as to formyl peptide receptor-1 (FPR1), which interacts with Annexin A1 (ANXA1) from dead cells. Breast cancer patients who bear loss-of-function alleles in TLR3, TLR4, and FPR1 exhibit a reduced metastasis-free and overall survival after treatment with anthracycline-based adjuvant chemotherapy. These genetic defects are epistatic with respect to each other, suggesting that they act on the same pathway, linking chemotherapy to a therapeutically relevant anticancer immune response. Loss-of-function alleles in TLR4 and FPR1 also affect the prognosis of colorectal cancer patients treated with oxaliplatin-based chemotherapy. Altogether, these results support the idea that conventional anticancer treatments rely on stimulation of anticancer immune responses to become fully efficient. Cancer Res; 76(11); 3122-6. Ó2016 AACR.

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“…Through a combination of all the available published data, it is hypothesized that a meta-analysis with increased statistical power might allow causative genes to be identified and plausible candidate genes to be excluded with reliability. Although there have been some meta-analyses focus on TLR4 polymorphism and CD, the relationship between TLR4 T399I gene polymorphism and the susceptibility to CD is controversial [20, 21]. Therefore, we conducted the present meta-analysis to quantitatively assess this relationship.…”

Section: Introductionmentioning

confidence: 99%

Association between Toll-Like Receptor 4 T399I Gene Polymorphism and the Susceptibility to Crohn’s Disease: A Meta-Analysis of Case-Control Studies

Shen

Lei

et al. 2018

Digestion

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Background/Aims: This article was undertaken to investigate the association of toll-like receptor 4 (TLR4) polymorphism (Thr399Ile) and risk of Crohn’s disease (CD) by performing a meta-analysis. Methods: Articles were chosen based on PubMed, Embase, China National Knowledge Internet, and Chinese Wanfang databases (up to 12th October 2016). Specific inclusion criteria were used to evaluate articles. Meta-analysis was performed by using a random or fixed effect model. Fifteen eligible case-control studies were finally included into this meta-analysis. We estimated the summary OR with its corresponding 95% CI to assess the association. Results: Summary results of this meta-analysis showed a moderate association between the TLR4 T399I polymorphism and the risk of CD (allele model: OR 1.26, 95% CI 1.06–1.50, p = 0.009; heterozygote model: OR 1.36, 95% CI 1.11–1.66, p = 0.003; dominant model: OR 1.35, 95% CI 1.10–1.64, p = 0.004; homozygote model: OR 1.08, 95% CI 0.44–2.64, p = 0.866; recessive model: OR 0.97, 95% CI 0.40–2.35, p = 0.946). Stratified analysis on geographical area, ethnicity, and genotypic methods suggested that the polymorphism was associated with increased risk of CD in Asia and Asians, and “T” allele only moderately increased CD risk within polymerase chain reaction-restricted fragment length polymorphism. Conclusions: Our meta-analysis suggests that TLR4 T399I polymorphism is moderately associated with susceptibility to CD, and more studies are needed to confirm our conclusion.

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Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis

Cited by 44 publications

References 58 publications

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy

Association between Toll-Like Receptor 4 T399I Gene Polymorphism and the Susceptibility to Crohn’s Disease: A Meta-Analysis of Case-Control Studies

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