文献紹介 腎におけるTLRシグナル

西部 里菜 Indigo Blue

PLoS One. 2012;7(5):e37584. Epub 2012 May 24.

TLR2, TLR4 and the MYD88 Signaling Pathway Are Crucial for Neutrophil Migration in Acute Kidney Injury Induced by Sepsis.
Castoldi A, Braga TT, Correa-Costa M, Aguiar CF, Bassi EJ, Correa-Silva R, Elias RM, Salvador F, Moraes-Vieira PM, Cenedeze MA, Reis MA, Hiyane MI, Pacheco-Silva A, Gonçalves GM, Câmara NO.

Source
Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Abstract
The aim of this study was to investigate the role of TLR2, TLR4 and MyD88 in sepsis-induced AKI. C57BL/6 TLR2(-/-), TLR4(-/-) and MyD88(-/-) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Twenty four hours later, kidney tissue and blood samples were collected for analysis. The TLR2(-/-), TLR4(-/-) and MyD88(-/-) mice that were subjected to CLP had preserved renal morphology, and fewer areas of hypoxia and apoptosis compared with the wild-type C57BL/6 mice (WT). MyD88(-/-) mice were completely protected compared with the WT mice. We also observed reduced expression of proinflammatory cytokines in the kidneys of the knockout mice compared with those of the WT mice and subsequent inhibition of increased vascular permeability in the kidneys of the knockout mice. The WT mice had increased GR1(+low) cells migration compared with the knockout mice and decreased in GR1(+high) cells migration into the peritoneal cavity. The TLR2(-/-), TLR4(-/-), and MyD88(-/-) mice had lower neutrophil infiltration in the kidneys. Depletion of neutrophils in the WT mice led to protection of renal function and less inflammation in the kidneys of these mice. Innate immunity participates in polymicrobial sepsis-induced AKI, mainly through the MyD88 pathway, by leading to an increased migration of neutrophils to the kidney, increased production of proinflammatory cytokines, vascular permeability, hypoxia and apoptosis of tubular cells.

論文紹介 Bcl10/Malt1 signaling pathway

総説1
Jost P, Peschel C, Ruland J. Curr Drug Targets. 2006;7:1335-40
The Bcl10/Malt1 signaling pathway as a drug target in lymphoma.

The development of lymphomas and leukemias is frequently caused by chromosomal translocations that deregulate cellular pathways of differentiation, proliferation or survival. The molecules that are involved in these aberrations provide rational targets for selective drug therapies. Recently, several disease specific translocations have been identified in human MALT lymphoma. These aberrations either upregulate the expression of BCL10 or MALT1 or induce the formation of API2-MALT1 fusion proteins. Genetic and biochemical experiments identified BCL10 and MALT1 as central components of an oligomerization-ubiquitinylation-phosphorylation cascade that activates the transcription factor NF-kappaB in response to antigen receptor ligation. Deregulation of the signaling cascade is directly associated with antigen independent MALT lymphoma growth. Here we provide an overview of the physiological and pathological functions of BCL10/MALT1 signal transduction and discuss the potential of this pathway as a drug target.


総説2
Klemm S, Ruland J. Immunobiology. 2006;211:815-20.
Inflammatory signal transduction from the Fc epsilon RI to NF-kappa B.

Mast cells are essential effector cells in IgE-associated immune responses. The major receptor for mast cell activation is the high affinity IgE receptor Fc epsilon RI. Fc epsilon RI crosslinking induces mast cell degranulation and de novo synthesis of potent proinflammatory mediators. Recent work identified Bcl10 and Malt1 as central regulators of a specific signaling pathway that controls NF-kappaB activation and proinflammatory cytokine production upon Fc epsilon RI ligation on mast cells. Bcl10 and Malt1 cooperate for the activation of this signaling cascade and selectively function downstream of PKC isoforms. However, Bcl10 and Malt1 are not involved in Fc epsilon RI- or PKC-induced signaling events that control degranulation or leukotriene synthesis. Thus, the Bcl10/Malt1 complex specifically uncouples the pathway for cytokine production from degranulation events. This review will summarize our current knowledge of the regulation of Fc epsilon RI-induced NF-kappaB activation in mast cells and discuss potential implications for allergic inflammatory diseases.

Bcl10を次回のジャーナルクラブで，プレゼンテーションできるようにしましょう！

Dectin-1と真菌症感染

Review
Nature Reviews Immunology 6, 33-43 (January 2006) | doi:10.1038/nri1745

Dectin-1: a signalling non-TLR pattern-recognition receptor
Gordon D. Brown1 About the author

Top of pageAbstractDectin-1 is a natural killer (NK)-cell-receptor-like C-type lectin that is thought to be involved in innate immune responses to fungal pathogens. This transmembrane signalling receptor mediates various cellular functions, from fungal binding, uptake and killing, to inducing the production of cytokines and chemokines. These activities could influence the resultant immune response and can, in certain circumstances, lead to autoimmunity and disease. As I discuss here, understanding the molecular mechanisms behind these functions has revealed new concepts, including collaborative signalling with the Toll-like receptors (TLRs) and the use of spleen tyrosine kinase (SYK), that have implications for the role of other non-TLR pattern-recognition receptors in immunity.

Am J Physiol Endocrinol Metab 286: E201-E207, 2004

Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response
Kenneth Feingold, Min Sun Kim, Judy Shigenaga, Art Moser, and Carl Grunfeld
Metabolism Section, Department of Medicine, University of California San Francisco, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121


Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPAR and PPAR, and TR and TR in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPAR coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase I, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXR, -, and -, PPAR and -, and TR and -, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.

Nature Medicine 11, 138 - 145 (2005)

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Karl S Lang, Mike Recher, Tobias Junt, Alexander A Navarini, Nicola L Harris, Stefan Freigang, Bernhard Odermatt, Curdin Conrad, Lars M Ittner, Stefan Bauer, Sanjiv A Luther, Satoshi Uematsu, Shizuo Akira, Hans Hengartner & Rolf M Zinkernagel

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8+ T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor−triggered interferon- production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

J Biol Chem. 2005 Jan 28

The interferon regulatory factor, IRF5, is a central mediator of TLR7 signaling.

Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM, Fitzgerald KA, Golenbock DT.

Department of Medicine, University of Massachusetts, Medical School, Worcester, MA 01605.

Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF-3 and IRF-7 are activated in response to a variety of viruses or following engagement of Toll-Like Receptor (TLR) 3 and TLR4 by double stranded RNA (dsRNA) and LPS, respectively. The activation of IRF-5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, IL-1 receptor associated kinase (IRAK) 1 and TNF-receptor associated factor (TRAF) 6 are required for the activation of IRF-5 and IRF-7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF-5 enabled type I interferon production in response to TLR7 signaling, while knockdown of IRF-5 by small interfering RNA (siRNA) reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF-5 and IRF-7 therefore emerge from these studies as critical mediators of TLR7 signaling.
IRF超重要

Immunol Cell Biol. 2005 Apr;83(2):196-8

Evidence of Toll-like receptor molecules on human platelets.

Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O.

The Auvergne-Loire Regional Blood Bank (EFS), Auvergne-Loire, France.

Summary Platelets are primarily involved in thrombosis and haemostasis, and they have recently been shown to have a role in innate immunity and in inflammation. We have determined the markers of innate immunity that are expressed by platelets, specifically the Toll-like receptors (TLR), originating from mixes of platelet concentrates (MPC, n = 5) between day zero and day five after blood collection. The surface membrane and intracellular expression of TLR were measured, both after and without permeabilization, using flow cytometry. We observed weak expression of TLR2, TLR4 and TLR9 on the surface of CD41(+) platelets. The expression levels of TLR4 were high (59 +/- 2.2%). Moreover, there was a significant expression of TLR2 (47.5 +/- 4.8%), TLR4 (78.8 +/- 1.3%) and TLR9 (34.2 +/- 7.5%) in the cytoplasm of CD41(+) platelets. The expression of the three receptors did not change significantly during the course of the 5 day observation period. The percentage of TLR expression is significantly modulated between activated versus non-activated platelets, both after and without permeabilization (P <0.01). Study of the expression of TLR could increase our knowledge of the level of platelet participation during an immune reaction and inflammation. In the same way as the platelet ligand/receptor pair CD40L/CD40 is, the TLR are expressed by platelets, and could serve as a link between innate and adaptive immunity.