[Frontiers in Bioscience 14, 2553-2558, January 1, 2009]
Role of Toll-like receptor mediated signaling pathway in ischemic heart
Yasuchika Takeishi1, Isao Kubota2
1
TABLE OF CONTENTS
1. ABSTRACT
Stimulation of TLRs by exogenous and endogenous ligands triggers expression of several genes that are involved in innate immune responses. Recently, a role of TLR4 in the myocardial response to injury separate from microbial pathogens has been examined in experimental studies. TLR4 deficient mice sustain significantly smaller infarctions compared with wild-type control mice given similar areas at risk. Levels of serum cytokines such as IL-1b, IL-6, and TNFa are increased after ischemia/reperfusion, but these responses are attenuated in TLR4 deficient mice compared to control mice. TLR2 signaling also importantly contributes to cardiac dysfunction following ischemia/reperfusion. MyD88, a key adaptor protein for TLR signaling, is responsible for the protective effects of TLR signaling inhibition in ischemia/reperfusion injury. TLR4 gene polymorphism (Asp299Gly) attenuates innate immune responsiveness, reduces the risk for coronary artery disease, and increases a chance of longevity. The innate immune system is clearly involved in the pathogenesis of cardiovascular diseases and could be a new therapeutic target.
2. INTRODUCTION
Host defense against invading microbial pathogens is elicited by the immune system, which consists of two approaches: innate immunity and acquired immunity (1). The innate immune system is limited to the recognition of evolutionary highly conserved pathogen motifs and is considered as a first line of defense (2, 3). The induction time of innate immune responses is fast. The innate immune response appears in primitive organisms in evolution. The Toll gene was first discovered as encoding for a receptor responsible for the dorsal ventral polarity in Drosophila (4). Toll was shown to be an essential receptor for host defense against fungal infection in Drosophila, which has only innate immunity. Subsequently, a mammalian homolog of the Toll receptor, Toll-like receptor (TLR), was identified to induce expression of genes involved in inflammatory responses (5). Recently, accumulating interest emerges from the cardiovascular research field in this TLR family (6). This review will focus on TLR signaling pathway in ischemic heart and ischemia/reperfusion injury.
3. EXPRESSIONS OF TLRS IN THE HEART AND VASCULATURE
Expression of the TLRs is very ubiquitous throughout species like mammals, fruit flies, chicken, and plants (7). Macrophages and T-lymphocytes express TLRs that recognize molecular patters that are foreign to mammalian organism but commonly found on pathogens (8). The principal effecter cells of innate immunity are macrophages, natural killer cells, and mast cells, and those cells play important roles in the development and progression of cardiovascular diseases. The macrophage secretes cytokines that guide and regulate function of other cells that are associated with atherogenesis and progression of atherosclerotic disease.
Expression of TLRs has been found in most cardiovascular cells such as cardiomyocytes (9), endothelial cells (10), adventitial fibroblasts (11), and dendritic cells (12). In neonatal rat cardiomyocytes, TLR2, TLR3, TLR4, and TLR6 are expressed (9). In murine myocardium, TLR4 expression is increased after myocardial infarction. Focal areas of intense TLR4 staining are observed in human heart tissue from patients with dilated cardiomyopathy (9, 13). Compared to cardiomyocytes, endothelial cells have about 5-fold higher TLR4 expression (9). Human endothelial cells express predominantly TLR4 and very low level of TLR2 (10). Lipopolysaccharide (LPS) and interferon (IFN)-g induce a 2-fold increase in TLR2 and TLR4 expression in endothelial cells (14). TLR2 and TLR4 are primarily expressed in endothelial cells and macrophages in the atherosclerotic lesions (15, 16).
4. TLR SIGNALING PATHWAY
Stimulation of TLRs by exogenous and endogenous ligands triggers expression of several genes that are involved in immune response. Ligand recognition by TLRs facilitates dimerization of TLRs (1, 2). Dimerization of TLRs triggers activation of signaling pathways, which originate from a cytoplasmic Toll/interleukin-1 receptor (TIR) domain (Figure 1). In the signaling pathways downstream of the TIR domain, a TIR domain-containing adaptor, myeloid differentiation factor 88 (MyD88), is essential for induction of inflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-4, IL-12, and IFN-g (17, 18). MyD88, harboring a C-terminal TIR domain and an N-terminal death domain, associates with the TIR domain of TLRs. Upon stimulation, MyD88 recruits IL-1 receptor associated kinase (IRAK)-4 to TLRs through interaction of both molecules, and facilitates IRAK-4-mediated phosphorylation of IRAK-1. Activated IRAK-1 then associates with TNF receptor associated factor 6 (TRAF6), leading to the activation of two distinct signaling pathways. One is activation of mitogen-activated protein (MAP) kinases, leading to AP-1 transcription factor. Another is the TAK1/TAB complex, which enhances activity of the IkB kinase (IKK) complex. The IKK complex induces phosphorylation and subsequent degradation of IkB, which then leads to nuclear translocation of NF-kB transcription factor.
In MyD88-deficient macrophages, TLR4 ligand-induced production of inflammatory cytokines is not observed, but activation of NF-kB is observed in the delayed phase (19). These data suggest that a MyD88 independent component exists in TLR4 signaling. TLR4 stimulation leads to activation of interferon regulatory factor 3 (IRF3) as well as the late phase activation of NF-kB in a MyD88-independent manner (20). Activation of IRF3 produces IFN-g.
5. ROLE OF TLR4 SIGNALING IN MYOCARDIAL ISCHEMIA/REPERFUSION
Currently, more than 10 mammalian TLRs have been discovered, and TLR4 is most extensively investigated among them. A point mutation in the TLR4 gene has been identified in a mouse strain (C3H/HeJ), which is unresponsive to LPS (21). The TLR4 mutant mouse enables us to investigate functional roles of TLR4 in vivo. In addition, immunologist Shizuo Akira of Osaka University in Japan and his colleagues deleted systemically the mouse genes for TLRs to reveal their specific functions (22). TLR4 is an essential receptor for recognition of LPS from Gram-negative bacteria, and also has been shown to recognize endogenous ligands such as heat shock proteins, fibronectins, and hyaluronic acid (6).
Recently, a role of TLR4 in the myocardial response to injury separate from microbial pathogens has been examined in experimental studies. Myocardial ischemia/reperfusion was performed on TLR4 mutant mice (23), which do not express functional TLR4 because of naturally occurring mutations in the TLR4 gene (21). Mice were subjected to 1 hour of coronary ligation followed by 24 hours of reperfusion. TLR4 mutant mice sustained significantly smaller infarctions compared with wild-type control mice given similar areas at risk. In TLR4 mutant mice, fewer neutrophils infiltrated into the myocardium, and fewer lipid peroxides and less complement deposition were contained compared with control mice after ischemia/reperfusion (23). These data suggest that TLR4 serves a proinflammatory role in murine myocardial ischemia/reperfusion injury. Levels of serum cytokines such as IL-1b, IL-6, and TNFa were increased after ischemia/reperfusion, but these responses were attenuated in TLR4 mutant mice compared to control mice (24). Although infarct size was smaller in TLR4 mutant mice following ischemia/reperfusion than in wild-type mice, left ventricular developed pressure measured with a left ventricular catheter was lower in TLR4 mutant mice. Thus, although the blockade of TLR4 signaling reduces myocardial infarction size and cytokine production, it does not preserve myocardial function (24).
A signaling cascade downstream of TLR4 was examined after ischemia/reperfusion using TLR4 mutant mice. After 1 hour of regional ischemia and 2 hours of reperfusion, significant activation of extra-cellular signal regulated kinase (ERK), p38 MAP kinase and c-Jun N-terminal kinase (JNK) was observed in wild-type mouse hearts (25). However in TLR4 mutant mice, JNK activity, but not ERK or p38 MAP kinase, was significantly reduced compared to wild-type mice. Nuclear translocation of NF-kB and AP-1 was significantly reduced in TLR4 mutant mice. IL-1b, monocyte chemotactic factor-1 (MCP-1), and IL-6 were detectable in reperfused ischemic myocardium, but the expression of these mediators was significantly decreased in the myocardial tissue of TLR4 mutant mice (25). A role of TLR4 in ischemia/reperfusion injury was also examined by pharmacological blockade of TLR4. Eritoran, a specific TLR4 antagonist, developed significantly smaller infarct size, reduction in JNK phosphorylation, less NF-kB translocation, and a decrease in cytokine expression after 30 minutes of ischemia and 120 minutes of reperfusion in mice (26).
Hua et al. examined the role of phosphoinositide 3-kinase (PI3K) and Akt signaling in TLR4-mediated cardioprotection following ischemia/reperfusion injury (27). TLR4 mutant mice and wild-type control mice were subjected to 45 minutes of ischemia followed by reperfusion for 4 hours. Pharmacological inhibition of PI3K with wortmannin or LY294002 abrogated myocardial protection in TLR4 mutant mice, suggesting that protection against myocardial ischemia/reperfusion injury in TLR4 mutant mice is mediated through a PI3K/Akt-dependent mechanism (27).
In a clinical study, expression of TLR4 on circulating monocytes from normal controls, patients with stable angina, unstable angina, and acute myocardial infarction was examined with the use of flow-cytometry (28). Circulating TLR4-positive monocytes were 2.5-fold increased above controls and patients with stable angina in patients with unstable angina and acute myocardial infarction. This was paralleled by enhanced transcript levels of TLR4 and MyD88 in patients with unstable angina and acute myocardial infarction. Acute coronary syndrome is associated with enhanced expression and signaling downstream of TLR4 in circulating monocytes.
6. FUNCTIONAL ROLE OF TLR2 IN ISCHEMIC HEARTS
TLR2 recognizes a variety of microbial components. These include lipoproteins from various pathogens, peptidoglycan and lipoteichoic acid from Gram-positive bacterias, soluble modulin, and yeast (6). The broad ligand specificity of TLR2 may be accounted by the fact that TLR2 dimerizes with other TLRs to detect optimally these ligands. In addition, it has been demonstrated that oxidative stress, an important factor for ischemia and ischemia/reperfusion injury, mediates nuclear translocation of NF-kB and AP-1 by a TLR2-dependent mechanism (29).
Recently, a functional role of TLR2 in response to ischemia- and ischemia/reperfusion-induced myocardial injury separate from microbial pathogens has been demonstrated in experimental studies using TLR2 knockout (KO) mice. Left anterior descending coronary artery was ligated in TLR2-KO mice and wild-type mice (30). Survival rate was significantly higher in TLR2-KO mice than in wild-type control mice 4 weeks after myocardial infarction. Although infarct size and degree of inflammatory cell infiltration in infarct area were similar, myocardial fibrosis in non-infarct area of TLR2-KO mice was much less compared to WT mice accompanied with reduced transforming growth factor-b1 and collagen type 1 mRNA expressions. One and four weeks after surgery, left ventricular dimensions at end-diastole and end-systole were smaller and fractional shortening was higher in TLR2-KO mice compared with control mice (30). These data suggest that TLR-2 plays an important role in ventricular remodeling after myocardial infarction.
TLR2 also mediates inflammation in response to non-infectious injury. Isolated cardiac function was examined in Langendorff-perfused hearts from TLR2 deficient mice and wild-type mice (31). Contractile performance after ischemia/reperfusion was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of left ventricular developed pressure relative to TLR2 deficient hearts. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNFa and IL-1b. Ischemia/reperfusion-induced cardiac dysfunction was reversed by treatment with the recombinant TNF blocking protein etanercept (31). TLR2 signaling importantly contributes to cardiac dysfunction following ischemia/reperfusion.
In TLR2 deficient mice, ischemia/reperfusion-induced endothelial dysfunction was improved compared to wild-type mice (32). TLR2 deficiency was also associated with a smaller infarct size and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration. TLR2 contributes to coronary endothelial dysfunction after ischemia/reperfusion, possibly through stimulation of neutrophil- and free radical-mediated endothelial injury.
7. MyD88 IS A KEY ADAPTOR PROTEIN FOR TLR SIGNALING
MyD88 is a key adaptor protein that plays a major role in the innate immune pathway (Figure 1). MyD88 contributes to cardiac inflammation and cytokine production after Coxsackie virus exposure (33). Hua et al. examined whether blocking the MyD88 could protect myocardium from ischemia/reperfusion injury by adenovirus-mediated transfection of dominant negative MyD88 into the myocardium of rats (34). The hearts were subjected to 45 minutes of ischemia and 4 hours of reperfusion at 3 days after adenovirus transfection. Dominant negative MyD88 significantly reduced infarct size compared with rat hearts transfected with GFP. Transfection of dominant negative MyD88 inhibited ischemia/reperfusion-induced NF-kB activation and increased the levels of Akt phosphorylation. The MyD88 blockade also attenuated cardiomyocyte apoptosis after ischemia/reperfusion (34). These data suggest that MyD88 is responsible for the protective effects of TLR signaling inhibition in ischemia/reperfusion injury.
8. CLINICAL SIGNIFICANCE OF TLR GENE POLYMORPHISM
TLR, the activity of which may be modulated by genetic polymorphisms, is a signaling receptor in innate immunity, and the inflammatory mediators produced by its activation exert various atherogenic effects. Kolek et al. examined whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory response, is associated with reduced vascular inflammation and a decreased risk for coronary artery disease in 1894 patients (35). The level of C-reactive protein was lower in G-allele carriers than wild-type (AA) subjects. G-allele carriers also had a lower prevalence of angiographic coronary artery disease. Another group studied the Asp299Gly polymorphism in 105 young Sicilian men admitted for acute myocardial infarction (mean age 41 years), 127 Sicilian men matched by age strata (mean age 38 years), and 55 Sicilian oldest old men (mean age 100 years) (36). The prevalence of G-allele carries was lower in patients with acute myocardial infarction and higher in the oldest old men compared to healthy young controls. These findings suggest that attenuation of innate immune responsiveness beneficially modifies the risk for coronary artery disease and increases a chance of longevity.
9. SUMMARY AND PERSPECTIVE
The innate immune system is clearly involved in the pathogenesis of cardiovascular diseases. New treatments could include drugs that block TLR4, TLR2 or MyD88 in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics. Such drugs might cripple a person's infection-fighting ability if delivered systemically, but administering them locally to the coronary arteries reduces that risk.
10. ACKNOWLEDGEMENTS
This study was supported in part by a grant-in-aid for Scientific Research (No. 19590804) from the Ministry of Education, Science, Sports and Culture, Japan.
11. REFERENCES
1. Kiyoshi Takeda and Shizuo Akira: Toll-like receptors in innate immunity. Int Immunol 17, 1-14 (2005)
2. Kiyoshi Takeda and Shizuo Akira: Toll-like receptor signaling. Nat Rev Immunol 4, 499-511 (2004)
3. Ingrid Wickelgren: Immunology. Targeting the tolls. Science 312, 184-187 (2006)
4. Bruno Lemaitre, Emmanuelle Nicolas, Lydia Michaut, Jean-Marc Reichhart, Jules A Hoffmann: The dorsovental regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973-983 (1996)
5. Ruslan Medzhitov, Paula Preston-Hurlburt, Charles A Janeway Jr: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397 (1997)
6. Dominique de Kleijn, Gerard Pasterkamp: Toll-like receptors in cardiovascular diseases. Cardiovasc Res 60, 58-67 (2003)
7. Egil Lien, Robin R Ingalls: Toll like receptors. Crit Care Med 30, S1-S11 (2002)
8. Charles A Janeway Jr, Ruslan Medzhitov: Innate immune recognition. Annu Rev Immunol 20, 197-216 (2002)
9. Stefan Frantz, Lester Kobzik, Young-Dae Kim, Ryuji Fukazawa, Ruslan Medzhitov, Richard T Lee, Ralph A. Kelly: Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104, 271-280 (1999)
10. Emmanuelle Faure, Ozlem Equils, Peter A Sieling, Lisa Thomas, Frank X Zhang, Carsten J Kirschning, Nadia Polentarutti, Marta Muzio, Moshe Arditi: Bacterial lipopolysaccharide activates NF-kB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 275, 11058-11063 (2000)
11. Aryan Vink, Arjan H Schoneveld, Jelger J van der Meer, Ben J van Middelaar, Joost PG Sluijter, Mirjam B Smeets, Paul HA Quax, Sai Kiang Lim, Cornelius Borst, Gerard Pasterkamp, Dominique PV de Kleijn: In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation 106, 1985-1990 (2002)
12. Katsuaki Hoshino, Tsuneyasu Kaisho, Tomio Iwabe, Osamu Takeuchi, Shizuo Akira: Differential involvement of IFN-b in Toll-like receptor-stimulated dendritic cell activation. Int Immunol 14, 1225-1231 (2002)
13. Mamoru Satoh, Motoyuki Nakamura, Tomonari Akatsu, Yudai Shimoda, Ikuo Segawa, Katsuhiko Hiramori: Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy. Lab Invest 84, 173-181 (2004)
14. Emmanuelle Faure, Lisa Thomas, Helen Xu, Andrei E Medvedev, Ozlem Equils, Moshe Arditi: Bacterial lipopolysaccharide and IFN-g induce Toll-like receptor 2 and Toll-like recptor 4 expression in human endothelial cells: Role of NF-kB activation. J Immunol 166, 2018-2024 (2001)
15. Xiaoou Helen Xu, Prediman K Shah, Emmanuelle Faure, Ozlem Equils, Lisa Thomas, Michael C Fishbein, Daniel Luthringer, Xiao-Ping Xu, Tripathi B Rajavashisth, Juliana Yano, Sanjay Kaul, Moshe Arditi: Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 104, 3103-3108 (2001)
16. Kristina Edfeldt, Jesper Swedenborg, Göran K Hansson, Zhong-qun Yan: Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105, 1158-1161 (2002)
17. Markus Schnare, Agnieszka Czopik Holt, Kiyoshi Takeda, Shizuo Akira, Ruslan Medzhitov: Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol 10, 1139-1142, (2000)
18. Hans Häcker, Ramunas M Vabulas, Osamu Takeuchi, Katsuaki Hoshino, Shizuo Akira, Hermann Wagner: Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF) 6. J Exp Med 192, 595-600 (2000)
19. Taro Kawai, Osamu Adachi, Tomohiko Ogawa, Kiyoshi Takeda, Shizuo Akira: Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115-122 (1999)
20. Taro Kawai, Osamu Takeuchi, Takashi Fujita, Jun-ichiro Inoue, Peter F Mühlradt, Shintaro Sato, Katsuaki Hoshino, Shizuo Akira: Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167, 5887-5894 (2001)
21. Alexander Poltorak, Xiaolong He, Irina Smirnova, Mu-Ya Liu, Christophe Van Huffel, Xin Du, Dale Birdwell, Erica Alejos, Maria Silva, Chris Galanos, Marina Freudenberg, Paola Ricciardi-Castagnoli, Betsy Layton, Bruce Beutler: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085-2088 (1998)
22. Kiyoshi Takeda, Tsuneyasu Kaisho, Shizuo Akira: Toll-like receptors. Annu Rev Immunol 21, 335-376 (2003)
23. Jun-ichi Oyama, Charles Blais Jr, Xiaoli Liu, Minying Pu, Lester Kobzik, Ralph A Kelly, Todd Bourcier: Reduced myocardial ischemia-reperfusion injury in Toll-like receptor-4 deficient mice. Circulation 109, 784-789 (2004)
24. Se-Chan Kim, Alexander Ghanem, Heidi Stapel, Klaus Tiemann, Pascal Knuefermann, Andreas Hoeft, Rainer Meyer, Christian Grohé, Anne A Knowlton, Georg Baumgarten: Toll-like receptor 4 deficiency: Smaller infarcts, but nogain in function. BMC Physiology 7, 5 (2007)
25 Albert J Chong, Akira Shimamoto, Craig R Hampton, Hiroo Takayama, Denise J Spring, Christine L Rothnie, Masaki Yada, Timothy H Pohlman, Edward D Verrier: Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128, 170-179 (2004)
26. Akira Shimamoto, Albert J Chong, Masaki Yada, Shin Shomura, Hiroo Takayama, Ani J Fleisig, Matthew L Agnew, Craig R Hampton, Christine L Rothnie, Denise J Spring, Timothy H Pohlman, Hideto Shimpo, Edward D Verrier: Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114 (suppl I), I-270-I-274 (2006)
27. Fang Hua, Tuanzhu Ha, Jing Ma, Yan Li, Jim Kelley, Xiang Gao, I William Browder, Race L Kao, David L Williams, Chuanfu Li: Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J Immunol 178, 7317-7324 (2007)
28. Heiko Methe, Jong-Oh Kim, Sieglinde Kofler, Michael Weis, Michael Nabauer, Joerg Koglin: Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 111, 2654-2661 (2005)
29. Stefan Frantz, Ralph A Kelly, Todd Bourcier: Role of TLR-2 in the activation of nuclear factor kB by oxidative stress in cardiac myocytes. J Biol Chem 276, 5197-5203 (2001)
30. Tetsuro Shishido, Naoki Nozaki, Seiji Yamaguchi, Yoko Shibata, Joji Nitobe, Takuya Miyamoto, Hiroki Takahashi, Takanori Arimoto, Kunihiko Maeda, Mitsunori Yamakawa, Osamu Takeuchi, Shizuo Akira, Yasuchika Takeishi, Isao Kubota: Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 108, 2905-2910 (2003)
31. Yasushi Sakata, Jian-Wen Dong, Jesus G Vallejo, Chien-Hua Huang, J Scott Baker, Kevin J Tracey, Osamu Tacheuchi, Shizuo Akira, Douglas L Mann: Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 292, H503-H509 (2007)
32. Julie Favre, Philippe Musette, Victorine Douin-Echinard, Karine Laude, Jean-Paul Henry, Jean-François Arnal, Christian Thuillez, Vincent Richard: Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction. Arterioscler Thromb Vasc Biol 27, 1064-1071 (2007)
33. Koichi Fuse, Grace Chan, Youan Liu, Patrick Gudgeon, Mansoor Husain, Manyin Chen, Wen-Chen Yeh, Shizuo Akira, Peter P Liu: Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112, 2276-2285 (2005)
34. Fang Hua, Tuanzhu Ha, Jing Ma, Xiang Gao, Jim Kelley, David L Williams, I William Browder, Race L Kao, Chuanfu Li: Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts. Biochem Biophys Res Commun 338, 1118-1125 (2005)
35. Matthew J Kolek, John F Carlquist, Joseph B Muhlestein, Bryant M Whiting, Benjamin D Horne, Tami L Bair, Jeffrey L Anderson: Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes. Am Heart J 148, 1034-1040 (2004)
36. Carmela Rita Balistreri, Giuseppina Candore, Giuseppina Colonna-Romano, Domenico Lio, Marco Caruso, Enrico Hoffmann, Claudio Franceschi, Calogero Caruso: Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 292, 2339-2340 (2004)
Abbreviations: TLR: Toll-like receptor; LPS: lipopolysaccharide; IFN: interferon; MyD88: myeloid differentiation factor 88; TNF: tumor necrosis factor; IL: interleukin; IRAK: IL-1 receptor associated kinase; TRAF6: TNF receptor associated factor 6; MAP: mitogen-activated protein; IKK: IkB kinase; IRF3: interferon regulatory factor 3; ERK: extra-cellular signal regulated kinase; JNK: c-Jun N-terminal kinase; MCP-1: monocyte chemotactic factor-1; PI3K: phosphoinositide 3-kinase; KO: knockout
Key Words MyD88, Signal transduction, NF-kB, Inflammation, Innate immunity, Cytokine, Review
Send correspondence to: Yasuchika Takeishi, First Department of Internal Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Japan 960-1295, Tel: 81-24-547-1188, Fax: 81-24-548-1821, E-mail:takeishi@fmu.ac.jp