TRIF–GEFH1–RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation

Kamon, Hokuto; Kawabe, Takahiro; Kitamura, Hiroyuki; Lee, Jihye; Kamimura, Daisuke; Kaisho, Tsuneyasu; Akira, Shizuo; Iwamatsu, Akihiro; Koga, Hisashi; Murakami, Masaaki; Hirano, Toshio

doi:10.1038/sj.emboj.7601286

Cited by 58 publications

(51 citation statements)

References 48 publications

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“…Since TLR4 can utilize the MyD88 and the TRIF pathways to deliver signaling, the finding that MyD88 deficiency did not abolish upregulation of CD80, CD86, CD40, and MHC II molecules suggests that TRIF participated in the modulation of DC maturation. This is in line with previous reports demonstrating that a MyD88-independent, but TRIF-dependent signaling pathway was responsible for the surface expression of MHC II and costimulatory molecules in LPS-activated DC (17,23). In the present study, we saw a higher expression of MHC II in MyD88 KO DC than in WT DC after BRD509(pSBRT7), BRD509, SBR, LPS, or Pam3CSK4 stimulation, suggesting that MyD88 signaling exerts an inhibitory effect on MHC II expression.…”

Section: Discussionsupporting

confidence: 82%

Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation

Katz

Zhang

et al. 2011

Infect Immun

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A Salmonella vector vaccine expressing the saliva-binding region (SBR) of the adhesin AgI/II of Streptococcus mutans has been shown to induce a mixed Th1/Th2 anti-SBR immune response in mice and to require Toll-like receptor 2 (TLR2), TLR4, and MyD88 signaling for the induction of mucosal anti-SBR antibody responses. Since dendritic cells (DC) are critical in innate and adaptive immunity, the present study assessed the role of SBR expression by the vector vaccine in DC activation. Bone marrow-derived DC from wild-type and TLR2, TLR4, and MyD88 knockout mice were stimulated with Salmonella vector BRD509, the SBR-expressing Salmonella vector vaccine BRD509(pSBRT7), or SBR protein, and the DC responses to different stimuli were compared by assessing costimulatory molecule expression, cytokine production, and signaling pathways. The DC response to both BRD509(pSBRT7) and BRD509 was dependent mainly on TLR4. BRD509(pSBRT7) and BRD509 induced upregulation of CD80, CD86, CD40, and major histocompatibility complex class II (MHC II) expression. Lower levels of interleukin-10 (IL-10) and IL-12p40 were produced by BRD509(pSBRT7)-stimulated DC than by BRD509-stimulated DC. Furthermore, BRD509(pSBRT7)-stimulated DC showed decreased p38 phosphorylation compared to that induced by DC stimulated with BRD509. However, BRD509(pSBRT7)-treated DC produced a higher level of IL-6 than BRD509-stimulated cells. The low IL-12p40 and high IL-6 cytokine profile expressed by BRD509(pSBRT7)-stimulated DC may represent a shift toward a Th2 response, as suggested by the increased expression in Jagged-1. These results provide novel evidence that a heterologous protein expressed by a Salmonella vector vaccine can differentially affect DC activation.

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Section: Discussionsupporting

confidence: 82%

Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation

Katz

Zhang

et al. 2011

Infect Immun

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“…administration of live or heat-killed E. coli in mice results in apoptosis of dendritic cells, and this process is mediated by TLR4 via a TRIF-dependent pathway and is independent of MyD88 (De Trez et al, 2005). Recently, a TRIF-specific and MyD88-independent pathway for TLR4 has been identified that provides a molecular mechanism relating how LPS induces major histocompatability class II expression during dendritic cell maturation (Kamon et al, 2006). It remains to be determined whether LPSmediated suppression of NRs and DMEs in the liver is controlled by a TRIF-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Ghose

White²,

Guo³

et al. 2007

Drug Metab Dispos

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ABSTRACT:During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor ␣ (RXR␣)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP ؉/؉ , and TIRAP ؊/؊ mice were injected i.p.with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed ϳ60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXR␣ were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1␤, tumor necrosis factor-␣, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-〉 was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP

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“…The stimulated cells were fixed in 4% paraformaldehyde for 20 min, permeabilized with Perm/Wash solution (BD Biosciences Cytofix/Cytoperm kit), and incubated with rabbit antip65 (1:50) for 1 h. After washing, the cells were incubated with anti-rabbit Alexa Fluor 488-conjugated secondary Ab (1:200) and Hoechst 33342 nuclear stain (1:10,000) for 1 h. Cells were then observed by confocal microscopy (22).…”

Section: Confocal Microscopymentioning

confidence: 99%

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng

Jiang

Atsumi

et al. 2016

The Journal of Immunology

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The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

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TRIF–GEFH1–RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation

Cited by 58 publications

References 48 publications

Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation

Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

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