Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity

Ahmed, Afsar U.; Williams, Bryan R.G.; Hannigan, Gregory E.

doi:10.3390/biom5043087

Cited by 44 publications

(37 citation statements)

References 118 publications

(147 reference statements)

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“…It has been reported that TAK1 activation leads to the activation of MAPK and NF-jB in TLR-3 signalling [25][26][27]. In colonic SEMFs, as shown in Fig.…”

Section: Poly(i:c) Activates Mapks Nf-jb and Activator Factor Proteimentioning

confidence: 79%

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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“…It has been reported that TAK1 activation leads to the activation of MAPK and NF-jB in TLR-3 signalling [25][26][27]. In colonic SEMFs, as shown in Fig.…”

Section: Poly(i:c) Activates Mapks Nf-jb and Activator Factor Proteimentioning

confidence: 79%

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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“…These results suggest that activation domains that have originated from plants may not able to work as efficiently away from the TATA box as exogenous activators (such as plant virus activators) (Douglas and Wendy 2015). Therefore, future work must focus on expanding the screening targets from plants to other symbiotic microbes (Afsar et al . 2015).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel efficient transcriptional activation domain from Chinese fir (Cunninghamia lanceolata)

Zhu

Tang

Chen³

et al. 2020

Preprint

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Activation domains are used as critical components of artificial gene modification tools for genetic breeding. The high efficiency of the activation domain relies on the host plant. However, no activation domain has been identified that originates from Chinese fir (Cunninghamia lanceolate). In this study, a novel strong activator was identified from the whole Chinese fir cDNA library. This plant conserved activator was named TAC 3 (Transcriptional Activation domain from Chinese fir 3). C-terminal 70 amino acids of TAC (TAC3d) have a stronger ability than the commonly used strong activation domain of the virus protein VP16, or the strong plant activation domain, EDLL, in Chinese fir. Through Dual-luciferase assay, phenomic analysis and FT (Flowering Locus T [FT]) quantification, it was shown that, TAC3d can overcome the transcriptional repression of strong plant repressors (Flowering Locus C [FLC]) when fused to its C-terminal domain, thus inhibit the repression of FT expression. In conclusion, for the first time, an activation domain has been identified from Chinese fir. TAC3, which can be used for precise gene activation in Chinese fir in the future, and its function in the plant is more powerful than the commonly used strong activation domain (such as VP16 and EDLL).HighlightTAC3 is the first transcriptional activation domain identified from Chinese fir and its function is more powerful than some commonly used strong transcriptional activators (such as VP16 and EDLL)

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“…Journal of Virology most likely alters sparse regions of the chromatin (87). Furthermore, the one-shot analysis done at 24 h will not mirror the dynamic changes over time (88).…”

Section: Tlr8 Agonist and Prostratin Activate Latent Hivmentioning

confidence: 99%

Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV

Rochat

Schlaepfer

Speck

2017

J Virol

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The persistence of latently HIV-infected cells in patients under combined antiretroviral treatment (cART) remains the major hurdle for HIV eradication. Thus far, individual compounds have not been sufficiently potent to reactivate latent virus and guarantee its elimination in vivo. Thus, we hypothesized that transcriptional enhancers, in concert with compounds triggering the innate immune system, are more efficient in reversing latency by creating a Th1 supportive milieu that acts against latently HIV-infected cells at various levels. To test our hypothesis, we screened six compounds on a coculture of latently infected cells (J-lat) and monocyte-derived dendritic cells (MDDCs). The protein kinase C (PKC) agonist prostratin, with a Toll-like receptor 8 (TLR8) agonist, resulted in greater reversion of HIV latency than any single compound. This combinatorial approach led to a drastic phenotypic and functional maturation of the MDDCs. Tumor necrosis factor (TNF) and cell-cell interactions were crucial for the greater reversion observed. Similarly, we found a greater potency of the combination of prostratin and TLR8 agonist in reversing HIV latency when applying it to primary cells of HIV-infected patients. Thus, we demonstrate here the synergistic interplay between TLR8-matured MDDCs and compounds acting directly on latently HIV-infected cells, targeting different mechanisms of latency, by triggering various signaling pathways. Moreover, TLR8 triggering may reverse exhaustion of HIV-specific cytotoxic T lymphocytes that might be essential for killing or constraining the latently infected cells. IMPORTANCE Curing HIV is the Holy Grail. The so-called "shock and kill" strategy relies on drug-mediated reversion of HIV latency and the subsequent death of those cells under combined antiretroviral treatment. So far, no compound achieves efficient reversal of latency or eliminates this latent reservoir. The compounds may not target all of the latency mechanisms in all latently infected cells. Moreover, HIVassociated exhaustion of the immune system hinders the efficient elimination of the reactivated cells. In this study, we demonstrated synergistic latency reversion by combining agonists for protein kinase C and Toll-like receptor 8 in a coculture of latently infected cells with myeloid dendritic cells. The drug prostratin stimulates directly the transcriptional machinery of latently infected cells, and the TLR8 agonist acts indirectly by maturing dendritic cells. These findings highlight the importance of the immune system and its activation, in combination with direct-acting compounds, to reverse latency.

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Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity

Cited by 44 publications

References 118 publications

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

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

Identification of a novel efficient transcriptional activation domain from Chinese fir (Cunninghamia lanceolata)

Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV

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