TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

Ahmed, Sibtain; Maratha, Ashwini; Butt, Aisha Qasim; Shevlin, Enda; Miggin, Sinéad M.

doi:10.4049/jimmunol.1201630

Cited by 38 publications

(31 citation statements)

References 59 publications

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“…In colonic SEMFs, the TLR-3 ligand [poly(I:C)] stimulated LL-37 expression. Previous studies reported that the TLR adaptor molecule (TRIF) facilitates TLR-3 signalling and concomitant activation of the transcription factors, NF-jB and AP-1, leading to proinflammatory cytokine production [28,36]. In this study, we demonstrated for the first time that the TLR-3-mediated intracellular signalling pathway leading to LL-37 expression required the formation of a complex of adaptor proteins, TRIF, TRAF6 and TAK1 in human colonic SEMFs.…”

Section: Ll-37 Expression In Ibdmentioning

confidence: 58%

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

Kusaka

Nishida

Takahashi

et al. 2017

Clinical and Experimental Immunology

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Summary Cathelicidin peptide LL-37 plays an important role in the early host response against invading pathogens via its broad-spectrum anti-microbial activity. In this study, we investigated LL-37 expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, the regulatory mechanism of LL-37 induction was investigated in human colonic subepithelial myofibroblasts (SEMFs). LL-37 mRNA expression and protein secretion were analysed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Intracellular signalling pathways were analysed using immunoblotting and specific small interference RNA (siRNA). The expression of LL-37 mRNA was increased significantly in the inflamed mucosa of ulcerative colitis and Crohn's disease. The Toll-like receptor (TLR)-3 ligand, polyinosinic-polycytidylic acid (poly(I:C), induced LL-37 mRNA expression and stimulated LL-37 secretion in colonic SEMFs. The transfection of siRNAs specific for intracellular signalling proteins [Toll/IL-1R domain-containing adaptor-inducing interferon (IFN) (TRIF), tumour necrosis factor receptor-associated factor (TRAF)6, transforming growth factor β-activated kinase (TAK)1] suppressed the poly(I:C)-induced LL-37 mRNA expression significantly. Poly(I:C)-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and activated nuclear factor kappa B (NF-κB) and activating factor protein (AP)-1. siRNAs specific for NF-κB and c-Jun inhibited poly(I:C)-induced LL-37 mRNA expression. LL-37 suppressed lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8 expression significantly in colonic SEMFs. The expression of LL-37 was up-regulated in the inflamed mucosa of IBD patients. LL-37 was induced by TLR-3 stimulation and exhibited an anti-microbial effect via interaction with lipopolysaccharide (LPS).

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Section: Ll-37 Expression In Ibdmentioning

confidence: 58%

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

Kusaka

Nishida

Takahashi

et al. 2017

Clinical and Experimental Immunology

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“…The Flag-TRIF was as described [17]. The plasmids pcDNA3: MyD88-cmyc, Flag-TRAM and TRAM-G2A were generously provided by Professor Luke O’Neill (Trinity College Dublin).…”

Section: Methodsmentioning

confidence: 99%

The TIR-Domain Containing Adaptor TRAM Is Required for TLR7 Mediated RANTES Production

Shevlin

Miggin

2014

PLoS ONE

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Toll-like receptor 7 (TLR7) plays a vital role in the immune response to ssRNA viruses such as human rhinovirus (HRV) and Influenza, against which there are currently no treatments or vaccines with long term efficacy available. Clearly, a more comprehensive understanding of the TLR7 signaling axis will contribute to its molecular targeting. TRIF related adaptor molecule (TRAM) plays a vital role in TLR4 signaling by recruiting TRIF to TLR4, followed by endosomal trafficking of the complex and initiation of IRF3 dependent type I interferon production as well as NF-κB dependent pro-inflammatory cytokine production. Towards understanding the molecular mechanisms that regulate TLR7 functionality, we found that TRAM−/− murine macrophages exhibited a transcriptional and translational impairment in TLR7 mediated RANTES, but not TNFα, production. Suppression of TRAM expression in human macrophages also resulted in an impairment in TLR7 mediated CCL5 and IFN-β, but not TNFα, gene induction. Furthermore, suppression of endogenous human TRAM expression in human macrophages significantly impaired RV16 induced CCL5 and IFNβ, but not TNFα gene induction. Additionally, TRAM-G2A dose-dependently inhibited TLR7 mediated activation of CCL5, IFNβ and IFNα reporter genes. TLR7-mediated phosphorylation and nuclear translocation of IRF3 was impaired in TRAM−/− cells. Finally, co-immunoprecipitation studies indicated that TRAM physically interacts with MyD88 upon TLR7 stimulation, but not under basal conditions. Our results clearly demonstrate that TRAM plays a, hitherto unappreciated, role in TLR7 signaling through a novel signaling axis containing, but not limited to, MyD88, TRAM and IRF3 towards the activation of anti-viral immunity.

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“…Finally, more recent progress in the biology of the IFN system points to epigenetic modulations as another component of IFN-induced innate immune response, suggesting the existence of a not yet fully explored “epigenetic signature” in genes activated by IFNs [124,125,126]. …”

Section: Type I Ifn Signaturementioning

confidence: 99%

Type I Interferons as Regulators of Human Antigen Presenting Cell Functions

Gessani

Conti

Cornò

et al. 2014

Toxins

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Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.

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TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

Cited by 38 publications

References 59 publications

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

The TIR-Domain Containing Adaptor TRAM Is Required for TLR7 Mediated RANTES Production

Type I Interferons as Regulators of Human Antigen Presenting Cell Functions

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