Pivotal Role of ADP-ribosylation Factor 6 in Toll-like Receptor 9-mediated Immune Signaling

Wu, Jing-Yiing; Kuo, Cheng-Chin

doi:10.1074/jbc.m111.295113

Cited by 27 publications

(37 citation statements)

References 42 publications

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“…We find that TLR2-dependent NF-B activation is also independent of Arf6. In contrast, TLR9-dependent NF-B activation is strongly dependent on Arf6, as Arf6 regulates the internalization of CpG DNA (25,27). In this study, we show a similar effect of Arf6 on internalization of LPS, showed that Rab11a is required for transport of TLR4, Trif, Tram, and IRF3 to E. coli phagosomes (47).…”

Section: Discussionmentioning

confidence: 52%

“…In a similar way, TLR9 requires internalization of its ligand CpG DNA. Arf6 regulates this internalization of CpG DNA and is essential for TLR9 MyD88-dependent signal transduction (25). We therefore tested whether Arf6 modulation also affects the internalization of LPS.…”

Section: Blocking Arf6 Strongly Inhibits Lps-induced Irf3 Phosphorylamentioning

confidence: 99%

“…Recently, Arf6 was shown to be essential for two receptors that are related to TLR4. Arf6 is required for TLR9 signaling via the regulation of cellular uptake of CpG oligodeoxynucleotides (ODN) (25). Arf6 also mediates interleukin-1␤ (IL-1␤) induced vascular endothelium stability (26).…”

mentioning

confidence: 99%

“…Arf6 also mediates interleukin-1␤ (IL-1␤) induced vascular endothelium stability (26). Both TLR9 and the IL-1␤ receptor use MyD88, but not Mal for their signal transduction (25)(26)(27).…”

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confidence: 99%

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The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

Acker

Eyckerman

Walle

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 52%

Section: Blocking Arf6 Strongly Inhibits Lps-induced Irf3 Phosphorylamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

Acker

Eyckerman

Walle

et al. 2014

Journal of Biological Chemistry

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“…The assay was developed according to a method previously described (39). The detailed procedure is provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Cheng¹,

Kuo²,

Yan³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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121

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Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.tumor suppression | tryptophan metabolism | inflammation control C yclooxygenase-2 (COX-2) is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities. It is involved in multiple physiological functions and triggers key pathological processes, such as tumorigenesis and inflammation (1, 2). COX-2 is constitutively overexpressed in a wide variety of human cancers and is enhanced by proinflammatory stimuli (3, 4). There is convincing evidence for a causal role of COX-2 in tumorigenesis. Inhibition of COX-2 activities was reported to control human colorectal cancer (5-8). COX-2 induces tumorigenesis by promoting important cellular functions including cell proliferation, migration, and resistance to apoptosis (9-11). The induced COX-2 expression by proinflammatory and mitogenic factors in normal cells is tightly controlled (12) whereas its overexpression in cancer cells is attributed to dysregulated transcription (13). The endogenous control mechanisms for COX-2 expression in normal cells and the mechanisms underlying the dysregulation in cancer cells are poorly understood. We previously identified in the conditioned medium of human fibroblasts small molecules (named cytoguardins) that suppress COX-2 expression induced by proinflammatory mediators (14). NMR analysis of a semipurified fraction revealed compounds with indole moieties (14). However, the exact chemical structures remain elusive. In this study, we elucidated the structure of cytoguardins by comparing the metabolomic profiles between normal and cancer cells. ResultsCytoguardins Inhibit Cancer Cell COX-2. To determine that fibroblast factors are capable of suppressing cancer cell COX-2 expression, we cocultured human Hs68 foreskin fibroblasts (HsFb) with A549 lung cancer cells in a Boyden chamber for 24 h. A549 cells were removed and treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and COX-2 proteins were analyzed. HsFb suppressed A549 ...

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Evolutionary history of disease‐susceptibility loci identified in longitudinal exome‐wide association studies

Yasukochi

Sakuma

Takeuchi

et al. 2019

Molec Gen & Gen Med

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Background Our longitudinal exome‐wide association studies previously detected various genetic determinants of complex disorders using ~26,000 single‐nucleotide polymorphisms (SNPs) that passed quality control and longitudinal medical examination data (mean follow‐up period, 5 years) in 4884–6022 Japanese subjects. We found that allele frequencies of several identified SNPs were remarkably different among four ethnic groups. Elucidating the evolutionary history of disease‐susceptibility loci may help us uncover the pathogenesis of the related complex disorders. Methods In the present study, we conducted evolutionary analyses such as extended haplotype homozygosity, focusing on genomic regions containing disease‐susceptibility loci and based on genotyping data of our previous studies and datasets from the 1000 Genomes Project. Results Our evolutionary analyses suggest that derived alleles of rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs closely located at 12q24.1 associated with type 2 diabetes mellitus, obesity, dyslipidemia, and three complex disorders (hypertension, hyperuricemia, and dyslipidemia), respectively, rapidly expanded after the human dispersion from Africa (Out‐of‐Africa). Allele frequencies of GGA3 and six SNPs at 12q24.1 appeared to have remarkably changed in East Asians, whereas the derived alleles of rs34902660 of SLC17A3 and rs7656604 at 4q13.3 might have spread across Japanese and non‐Africans, respectively, although we cannot completely exclude the possibility that allele frequencies of disease‐associated loci may be affected by demographic events. Conclusion Our findings indicate that derived allele frequencies of nine disease‐associated SNPs (rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs at 12q24.1) identified in the longitudinal exome‐wide association studies largely increased in non‐Africans after Out‐of‐Africa.

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Pivotal Role of ADP-ribosylation Factor 6 in Toll-like Receptor 9-mediated Immune Signaling

Cited by 27 publications

References 42 publications

The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Evolutionary history of disease‐susceptibility loci identified in longitudinal exome‐wide association studies

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