Post by Max on Sept 21, 2005 13:20:18 GMT -5
Toll-like receptors (TLR) and macrophage activation
Thirteen TLRs have been described to date, each which recognize specific pathogen-associated molecular patterns [2]. Macrophages recognize the presence of infection by using the Toll-like receptor (TLR) family of proteins that detect ligands on bacterial, viral, and fungal pathogens. TLR signaling, through the MyD88 adaptor, up-regulates transcription of the retinoic acid early inducible-1 (RAE-1) family of NKG2D ligands, but not H-60 or murine UL16-binding protein-like transcript-1 [1]. Mast cells mediate both IgE-dependent allergic reactions and protective responses against acute infections possibly through the activation of Toll-like receptors (TLRs). Antigen interacts synergistically with TLR2 and TLR4 ligands to markedly enhance production of cytokines in murine mast cell lines. The suggested regulation of cytokine production could be attributed to synergistic activation of mitogen activated protein kinases in addition to the engagement of a more effective repertoire of transcription factors for cytokine gene transcription. The synergistic interactions of TLR ligands and antigen might have relevance to the exacerbation of IgE-mediated allergic diseases by infectious agents [2].
While the Toll-like receptor (TLR) system is innate immunity's sensor of infectious danger, macrophages receive activating as well as inhibitory signals via the Jak-Stat pathway. IFNgamma is key to the control of infection particularly with intracellular pathogens and depends on functional Stat1 signal transduction. Stat3 signalling is activated by a range of cytokines, including IL-10, IL-6 and IL-27 [3].
Significant interaction between the nuclear receptor family and the toll like receptors
Cell. 2005 Sep 9;122(5):707-21. Related Articles, Links
Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors.
Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK.
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093.
Nuclear receptors (NRs) repress transcriptional responses to diverse signaling pathways as an essential aspect of their biological activities, but mechanisms determining the specificity and functional consequences of transrepression remain poorly understood. Here, we report signal- and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages. The glucocorticoid receptor (GR) represses a large set of functionally related inflammatory response genes by disrupting p65/interferon regulatory factor (IRF) complexes required for TLR4- or TLR9-dependent, but not TLR3-dependent, transcriptional activation. This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression. PPARgamma and LXRs repress overlapping transcriptional targets by p65/IRF3-independent mechanisms and cooperate with the GR to synergistically transrepress distinct subsets of TLR-responsive genes. These findings reveal combinatorial control of homeostasis and immune responses by nuclear receptors and suggest new approaches for treatment of inflammatory diseases.
PMID: 16143103 [PubMed - in process]
Thirteen TLRs have been described to date, each which recognize specific pathogen-associated molecular patterns [2]. Macrophages recognize the presence of infection by using the Toll-like receptor (TLR) family of proteins that detect ligands on bacterial, viral, and fungal pathogens. TLR signaling, through the MyD88 adaptor, up-regulates transcription of the retinoic acid early inducible-1 (RAE-1) family of NKG2D ligands, but not H-60 or murine UL16-binding protein-like transcript-1 [1]. Mast cells mediate both IgE-dependent allergic reactions and protective responses against acute infections possibly through the activation of Toll-like receptors (TLRs). Antigen interacts synergistically with TLR2 and TLR4 ligands to markedly enhance production of cytokines in murine mast cell lines. The suggested regulation of cytokine production could be attributed to synergistic activation of mitogen activated protein kinases in addition to the engagement of a more effective repertoire of transcription factors for cytokine gene transcription. The synergistic interactions of TLR ligands and antigen might have relevance to the exacerbation of IgE-mediated allergic diseases by infectious agents [2].
While the Toll-like receptor (TLR) system is innate immunity's sensor of infectious danger, macrophages receive activating as well as inhibitory signals via the Jak-Stat pathway. IFNgamma is key to the control of infection particularly with intracellular pathogens and depends on functional Stat1 signal transduction. Stat3 signalling is activated by a range of cytokines, including IL-10, IL-6 and IL-27 [3].
Significant interaction between the nuclear receptor family and the toll like receptors
Cell. 2005 Sep 9;122(5):707-21. Related Articles, Links
Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors.
Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK.
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093.
Nuclear receptors (NRs) repress transcriptional responses to diverse signaling pathways as an essential aspect of their biological activities, but mechanisms determining the specificity and functional consequences of transrepression remain poorly understood. Here, we report signal- and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages. The glucocorticoid receptor (GR) represses a large set of functionally related inflammatory response genes by disrupting p65/interferon regulatory factor (IRF) complexes required for TLR4- or TLR9-dependent, but not TLR3-dependent, transcriptional activation. This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression. PPARgamma and LXRs repress overlapping transcriptional targets by p65/IRF3-independent mechanisms and cooperate with the GR to synergistically transrepress distinct subsets of TLR-responsive genes. These findings reveal combinatorial control of homeostasis and immune responses by nuclear receptors and suggest new approaches for treatment of inflammatory diseases.
PMID: 16143103 [PubMed - in process]