The Experts below are selected from a list of 36228 Experts worldwide ranked by ideXlab platform
Norimitsu Inoue - One of the best experts on this subject based on the ideXlab platform.
-
protein kinase cδ binds tirap mal to participate in TLR Signaling
Molecular Immunology, 2007Co-Authors: Miho Kubomurai, Kaoru Hazeki, Naoe Sukenobu, Kyoko Yoshikawa, Kiyomi Nigorikawa, Kazumi Inoue, Toshiyoshi Yamamoto, Misako Matsumoto, Tsukasa Seya, Norimitsu InoueAbstract:Toll-like receptor (TLR) family members recognize specific molecular patterns within pathogens. Signaling through TLRs results in a proximal event that involves direct binding of adaptor proteins to the receptors. We observed that TIRAP/Mal, an adaptor protein for TLR2 and TLR4, binds protein kinase Cdelta (PKCdelta). TIRAP/Mal GST-fusion protein and a TIRAP/Mal antibody were able to precipitate PKCdelta from rat peritoneal macrophage and THP1 cell lysates. Truncation mutants of TIRAP/Mal showed that the TIR domain of TIRAP/Mal is responsible for binding. TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IkappaB in RAW264.7 cells were abolished by depletion of PKCdelta. These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR Signaling events.
-
Protein kinase Cδ binds TIRAP/Mal to participate in TLR Signaling
Molecular Immunology, 2007Co-Authors: Miho Kubo-murai, Kaoru Hazeki, Naoe Sukenobu, Kyoko Yoshikawa, Kiyomi Nigorikawa, Kazumi Inoue, Toshiyoshi Yamamoto, Misako Matsumoto, Tsukasa Seya, Norimitsu InoueAbstract:Toll-like receptor (TLR) family members recognize specific molecular patterns within pathogens. Signaling through TLRs results in a proximal event that involves direct binding of adaptor proteins to the receptors. We observed that TIRAP/Mal, an adaptor protein for TLR2 and TLR4, binds protein kinase Cdelta (PKCdelta). TIRAP/Mal GST-fusion protein and a TIRAP/Mal antibody were able to precipitate PKCdelta from rat peritoneal macrophage and THP1 cell lysates. Truncation mutants of TIRAP/Mal showed that the TIR domain of TIRAP/Mal is responsible for binding. TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IkappaB in RAW264.7 cells were abolished by depletion of PKCdelta. These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR Signaling events.
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
-
Maternal TLR Signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78.
The Journal of experimental medicine, 2009Co-Authors: M. L. Conrad, Shizuo Akira, Ruth Ferstl, R. Teich, Stephanie Brand, Nicole Blümer, Ali Ö. Yildirim, Cecilia C. Patrascan, Anna Hanuszkiewicz, Hermann WagnerAbstract:The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) Signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR Signaling was tested in TLR2/3/4/7/9−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR Signaling, and asthma protection in the progeny.
-
TLR Signaling fine tunes anti influenza b cell responses without regulating effector t cell responses
Journal of Immunology, 2007Co-Authors: Alex K Heer, Abdijapar Shamshiev, Alena Donda, Satoshi Uematsu, Shizuo Akira, Manfred Kopf, Benjamin J MarslandAbstract:Influenza is a ssRNA virus that has been responsible for widespread morbidity and mortality; however, the innate immunological mechanisms that drive the adaptive anti-influenza immune response in vivo are yet to be fully elucidated. TLRs are pattern recognition receptors that bind evolutionarily conserved pathogen-associated molecular patterns, induce dendritic cell maturation, and consequently aid the development of effective immune responses. We have examined the role of TLRs in driving effective T and B cell responses against influenza virus. We found TLR3 and its associated adapter molecule, Toll/IL-R domain-containing adaptor-inducing IFN-beta, did not play a role in the development of CD4(+) or CD8(+) T cell responses against influenza virus, nor did they influence influenza-specific B cell responses. Surprisingly, TLR7 and MyD88 also played negligible roles in T cell activation and effector function upon infection with influenza virus; however, their Signaling was critical for regulating anti-influenza B cell Ab isotype switching. The induction of appropriate anti-influenza humoral responses involved stimulation of TLRs on B cells directly and TLR-induced production of IFN-alpha, which acted to reduce IgG1 and increase IgG2a/c class switching. Notably, direct TLR Signaling on B cells or T cell help through the CD40-CD40L interaction was sufficient to support B cell proliferation and IgG1 production, whereas IFN-alpha was critical for fine-tuning the nature of the isotype switch. Taken together, these data reveal that TLR Signaling is not required for anti-influenza T cell responses, but through both direct and indirect means orchestrates appropriate anti-influenza B cell responses.
-
TLR Signaling PATHWAYS
Seminars in immunology, 2004Co-Authors: Kiyoshi Takeda, Shizuo AkiraAbstract:Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLR Signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR Signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR Signaling.
-
TIR domain-containing adaptors define the specificity of TLR Signaling.
Molecular immunology, 2004Co-Authors: Masahiro Yamamoto, Kiyoshi Takeda, Shizuo AkiraAbstract:The concept that Toll-like receptors (TLRs) recognize specific molecular patterns in various pathogens has been established. In signal transduction via TLRs, MyD88, which harbors a Toll/IL-1 receptor (TIR)-domain and a death domain, has been shown to link between TLRs and MyD88-dependent downstream events leading to proinflammatory cytokine production and splenocyte proliferation. However, recent studies using MyD88-deficient mice have revealed that some TLRs possess a MyD88-independent pathway, which is represented by interferon (IFN)-beta production induced by LPS stimulation. This indicates that additional Signaling molecules other than MyD88 exist in the TLR Signaling pathway. Indeed, two additional TIR domain-containing adaptors, TIRAP/Mal and TRIF, have recently been identified. Both define the specific biological responses of each TLR.
Bostjan Kobe - One of the best experts on this subject based on the ideXlab platform.
-
trif dependent TLR Signaling its functions in host defense and inflammation and its potential as a therapeutic target
Journal of Leukocyte Biology, 2016Co-Authors: Obayed M Ullah, Matthew J Sweet, Ashley Mansell, Stuart Kellie, Bostjan KobeAbstract:Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent Signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the Signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF Signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR Signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR Signaling for therapeutic benefit.
-
TRIF‐dependent TLR Signaling, its functions in host defense and inflammation, and its potential as a therapeutic target
Journal of leukocyte biology, 2016Co-Authors: M. Obayed Ullah, Matthew J Sweet, Ashley Mansell, Stuart Kellie, Bostjan KobeAbstract:Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent Signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the Signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF Signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR Signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR Signaling for therapeutic benefit.
Barbara Detrick - One of the best experts on this subject based on the ideXlab platform.
-
Innate immunity in the retina: Toll-like receptor (TLR) Signaling in human retinal pigment epithelial cells.
Journal of Neuroimmunology, 2004Co-Authors: Matam Vijay Kumar, Chandrasekharam N. Nagineni, M.s. Chin, John J. Hooks, Barbara DetrickAbstract:Abstract Toll-like receptors (TLRs) are crucial components of innate immunity that participate in host defense against microbial pathogens. We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. Real time PCR analysis revealed gene expression for TLRs 1–7, 9, and 10 in RPE cells. TLRs 1 and 3 were the most highly expressed TLRs. Protein expression for TLRs 2, 3, and 4 was observed on RPE cells and this expression was augmented by treatment with poly I:C or interferon-γ (IFN-γ). TLR 3 is the receptor for dsRNA, an intermediate of virus replication. Because RPE cells express TLR 3 and are frequently the site of virus replication within the retina, we evaluated TLR 3 Signaling. RPE cells treated with poly I:C produced IFN-β but not IFN-α, and this was inhibited by the treatment of RPE cells with anti-TLR 3 antibody. Human recombinant IFN-β was shown to be biologically active on RPE cells by inhibiting viral replication. Poly I:C treatment of RPE resulted in an increase in the production of IL-6, IL-8, MCP-1, and sICAM-1. The presence of TLRs on RPE cells and the resultant TLR Signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina.
-
innate immunity in the retina toll like receptor TLR Signaling in human retinal pigment epithelial cells
Journal of Neuroimmunology, 2004Co-Authors: Matam Vijay Kumar, Chandrasekharam N. Nagineni, M.s. Chin, John J. Hooks, Barbara DetrickAbstract:Toll-like receptors (TLRs) are crucial components of innate immunity that participate in host defense against microbial pathogens. We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. Real time PCR analysis revealed gene expression for TLRs 1-7, 9, and 10 in RPE cells. TLRs 1 and 3 were the most highly expressed TLRs. Protein expression for TLRs 2, 3, and 4 was observed on RPE cells and this expression was augmented by treatment with poly I:C or interferon-gamma (IFN-gamma). TLR 3 is the receptor for dsRNA, an intermediate of virus replication. Because RPE cells express TLR 3 and are frequently the site of virus replication within the retina, we evaluated TLR 3 Signaling. RPE cells treated with poly I:C produced IFN-beta but not IFN-alpha, and this was inhibited by the treatment of RPE cells with anti-TLR 3 antibody. Human recombinant IFN-beta was shown to be biologically active on RPE cells by inhibiting viral replication. Poly I:C treatment of RPE resulted in an increase in the production of IL-6, IL-8, MCP-1, and sICAM-1. The presence of TLRs on RPE cells and the resultant TLR Signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina.
Matam Vijay Kumar - One of the best experts on this subject based on the ideXlab platform.
-
Innate immunity in the retina: Toll-like receptor (TLR) Signaling in human retinal pigment epithelial cells.
Journal of Neuroimmunology, 2004Co-Authors: Matam Vijay Kumar, Chandrasekharam N. Nagineni, M.s. Chin, John J. Hooks, Barbara DetrickAbstract:Abstract Toll-like receptors (TLRs) are crucial components of innate immunity that participate in host defense against microbial pathogens. We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. Real time PCR analysis revealed gene expression for TLRs 1–7, 9, and 10 in RPE cells. TLRs 1 and 3 were the most highly expressed TLRs. Protein expression for TLRs 2, 3, and 4 was observed on RPE cells and this expression was augmented by treatment with poly I:C or interferon-γ (IFN-γ). TLR 3 is the receptor for dsRNA, an intermediate of virus replication. Because RPE cells express TLR 3 and are frequently the site of virus replication within the retina, we evaluated TLR 3 Signaling. RPE cells treated with poly I:C produced IFN-β but not IFN-α, and this was inhibited by the treatment of RPE cells with anti-TLR 3 antibody. Human recombinant IFN-β was shown to be biologically active on RPE cells by inhibiting viral replication. Poly I:C treatment of RPE resulted in an increase in the production of IL-6, IL-8, MCP-1, and sICAM-1. The presence of TLRs on RPE cells and the resultant TLR Signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina.
-
innate immunity in the retina toll like receptor TLR Signaling in human retinal pigment epithelial cells
Journal of Neuroimmunology, 2004Co-Authors: Matam Vijay Kumar, Chandrasekharam N. Nagineni, M.s. Chin, John J. Hooks, Barbara DetrickAbstract:Toll-like receptors (TLRs) are crucial components of innate immunity that participate in host defense against microbial pathogens. We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. Real time PCR analysis revealed gene expression for TLRs 1-7, 9, and 10 in RPE cells. TLRs 1 and 3 were the most highly expressed TLRs. Protein expression for TLRs 2, 3, and 4 was observed on RPE cells and this expression was augmented by treatment with poly I:C or interferon-gamma (IFN-gamma). TLR 3 is the receptor for dsRNA, an intermediate of virus replication. Because RPE cells express TLR 3 and are frequently the site of virus replication within the retina, we evaluated TLR 3 Signaling. RPE cells treated with poly I:C produced IFN-beta but not IFN-alpha, and this was inhibited by the treatment of RPE cells with anti-TLR 3 antibody. Human recombinant IFN-beta was shown to be biologically active on RPE cells by inhibiting viral replication. Poly I:C treatment of RPE resulted in an increase in the production of IL-6, IL-8, MCP-1, and sICAM-1. The presence of TLRs on RPE cells and the resultant TLR Signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina.
