TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

Wardill, Hannah R.; Gibson, Rachel J.; Logan, Richard M.; Bowen, Joanne M.

doi:10.1002/ijc.28656

Cited by 35 publications

(28 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several claudin genes were significantly affected and DOX-treated piglets showed enhancement of GO cellular component tight-junction gene set expressions, with claudin 3, 6, 11, 14, and 16 in the leading edge subset (nominal p value 0.011). These findings are supported by previous reports documenting changes in tight-junction protein composition, expression, and function following chemotherapy (table 1) [13,14,47]. The exact role of tight-junction proteins in mucositis, as well as their interaction with other mediators such as MMP and proinflammatory cytokines, is an area of intense investigation [47,48].…”

Section: Discussionsupporting

confidence: 75%

Chemotherapy Modulates Intestinal Immune Gene Expression Including Surfactant Protein-D and Deleted in Malignant Brain Tumors 1 in Piglets

Rathe¹,

Thomassen

Shen

et al. 2016

Chemotherapy

View full text Add to dashboard Cite

Background: Information about chemotherapy-induced intestinal gene expression may provide insight into the mechanisms underlying gut toxicity and help identify biomarkers and targets for intervention. Methods: We analyzed jejunal tissue from piglets subjected to two different, clinically relevant chemotherapy regimens: (1) busulfan plus cyclophosphamide (BUCY) and (2) doxorubicin (DOX). Results: Gene expression analysis identified 1,328 differentially expressed genes in the BUCY piglets and 594 in the DOX piglets, compared to controls. Similar changes in expression were found for 137 genes across the BUCY and DOX piglets. Selected genes of potential biological significance with a similar change in expression across the treatments were controlled by real-time polymerase chain reaction. Key innate defense molecules, including surfactant protein-D and deleted in malignant brain tumors 1, were among the upregulated genes for both treatments. Conclusion: In the developing intestine, chemotherapy increases the expression of genes related to innate immune functions involved in surveillance, protection, and homeostasis of mucosal surfaces.

show abstract

Section: Discussionsupporting

confidence: 75%

Chemotherapy Modulates Intestinal Immune Gene Expression Including Surfactant Protein-D and Deleted in Malignant Brain Tumors 1 in Piglets

Rathe¹,

Thomassen

Shen

et al. 2016

Chemotherapy

View full text Add to dashboard Cite

show abstract

“…When mucosal homeostasis is disrupted, PKC signalling participates in TLR-induced downstream events [20, 35, 36]. Cario et al suggested that TLR2 activation enhances ZO-1 via PKC, and Gibson et al reported that TLR2 plays a critical role in maintaining intestinal mucosal integrity during infections by bacterial pathogens.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Facilitates Toll-Like Receptor 4 Expression to Improve Intestinal Barrier Function through Retinoic Acid Receptor Beta

Gao

Cui

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Vitamin A (VA) protects the intestinal epithelial barrier by improving cell migration and proliferation. Our previous studies demonstrated that VA deficiency (VAD) during pregnancy suppresses the systemic and mucosal immune responses in the intestines of offspring and that VA supplementation (VAS) during early life can increase immune cell counts. However, little is known about the mechanisms by which VA regulates intestinal epithelial barrier function. Methods: Caco-2 cells were treated with all-trans retinoic acid (ATRA) for 24 hours to determine the optimum ATRA concentration to which the cells in question respond. Caco-2 cells were infected with recombinant adenoviruses carrying retinoic acid receptor beta (Ad-RARβ) and small interfering RARβ(siRARβ) to assess the effects of RARβ signalling on the expression of specific proteins. A siTLR4 lentivirus was used to knockdown Toll-like receptor 4 (TLR4) in Caco-2 cells to determine its role in the protective effects of VA on the intestinal epithelial barrier, and experiments involving TLR4-knock-out mice were performed to verify the effect of TLR4. VA normal (VAN), VAD and VAS rat models were established to confirm that changes in RARβ, TLR4 and ZO-2 expression levels that occurred following decreases or increases in retinol concentrations in vivo, and the permeability of the Caco-2 cell monolayer, as well as that of the epithelial barrier of the rat intestine was detected by measuring transepithelial resistance (TER) or performing enzyme-linked immunosorbent assay (ELISA). Retinoic acid receptor (RAR), toll like receptor (TLR) and tight junction (TJ) mRNA and protein expression levels in Caco-2 cells and the colon monolayers in the rat and mouse models were measured by PCR and western blotting, respectively. Co-immunoprecipitation (co-IP) and immunofluorescence staining were performed to assess the interactions among RARβ, TLR4 and zonula occluden-2 (ZO-2) in Caco-2 cells, and chromatin immunoprecipitation (ChIP) assay was performed to assess the binding between RARβ and the TLR4 promoter sequence in Caco-2 cells. Results: In the present study, ATRA treatment not only increased the TER of the Caco-2 monolayer but also up-regulated the expression levels of RARβ, TLR4 and ZO-2 in Caco-2 cells. The expression levels of these three proteins were significantly decreased in the colonic epithelial monolayers of VAD rats compared with those of VAN rats and were significantly increased following VAS in the corresponding group compared with the control group. Furthermore, the above changes in TLR4 and ZO-2 expression levels were augmented or attenuated by Ad-RARβ or siRARβ infection, respectively, in Caco-2 cells. Interestingly, siTLR4 down-regulated ZO-2 expression but did not affect RARβ expression in Caco-2 cells, and in VAD mice the lack of TLR4 did not affect ZO-2 expression. We noted direct interactions between RARβ and TLR4, TLR4 and ZO-2 in Caco-2 cells, and ChIP assay showed that RARβ could bind to the TLR4 promoter but not the ZO-2 promoter in Ca...

show abstract

“…In light of these findings, the interaction between the gut microbiome and innate mucosal immune system has also gained interest, with particular emphasis on the impact of toll-like receptor (TLR) signaling (8)(9)(10). TLRs are a family of transmembrane protein receptors recognising a diverse range of signals on exogenous and endogenous substances considered to be 'dangerous', and hence warranting activation of the innate immune system for host survival (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

Self Cite

122

124

View full text Add to dashboard Cite

Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

show abstract

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

Cited by 35 publications

References 120 publications

Chemotherapy Modulates Intestinal Immune Gene Expression Including Surfactant Protein-D and Deleted in Malignant Brain Tumors 1 in Piglets

Chemotherapy Modulates Intestinal Immune Gene Expression Including Surfactant Protein-D and Deleted in Malignant Brain Tumors 1 in Piglets

Retinoic Acid Facilitates Toll-Like Receptor 4 Expression to Improve Intestinal Barrier Function through Retinoic Acid Receptor Beta

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Contact Info

Product

Resources

About