THE ROLE OF THE NFκB PATHWAY IN ATHEROSCLEROSIS
|
|
- Robert Jordan Heath
- 6 years ago
- Views:
Transcription
1 THE ROLE OF THE NFκB PATHWAY IN ATHEROSCLEROSIS Claudia Monaco, Jennifer Grosjean, and Ewa Paleolog, Kennedy Institute of Rheumatology & Division of Surgery, Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College, London, U.K. Introduction Cardiovascular diseases are the leading cause of morbidity and mortality in Western countries. Although coronary thrombosis is the final event in acute coronary syndromes, there is increasing evidence that inflammation also plays a role in development of atherosclerosis and its clinical manifestations, such as myocardial infarction, stroke, and peripheral vascular disease. Many inflammatory genes relevant to atherosclerosis are influenced by the transcriptional regulator nuclear factor κ B (NFκB). The NfκB Signalling Pathway NFκB plays a pivotal role in co-ordinating the expression of genes involved in the immune and inflammatory response, for example cytokines, including tumor necrosis factor α (TNFα), chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-8, matrix metalloproteinase enzymes (MMP), and genes involved in cell survival. Mammalian cells contain homo- and hetero-dimers of NFκB subunits, generally sub-divided into those synthesized as mature forms (rela or p65, relb, and c-rel) and those made as large precursors (p105 and p100), which undergo proteolysis to produce mature DNA binding proteins (p50 and p52 respectively) [1,2]. In the so-called canonical activation pathway, IκB kinase (IKK)-2 (IKKβ) phosphorylates IκBα, leading to its ubiquitination and degradation, allowing NFκB to translocate to the nucleus [3]. This pathway is thought to be crucial for activation of innate immunity and inflammation in response to mediators such as TNFα. However, an alternative or non-canonical pathway has been described, under the control of NFκB-inducing kinase (NIK) and IKKα/IKK-1. In response to stimuli such as lymphotoxin β, NIK has been shown to activate IKK-1 leading to inducible processing of p100 with preferential nuclear translocation of p52- RelB dimers. This non-canonical pathway has been proposed to have a role in B-cell-mediated responses and adaptive humoral immunity [4]. Atherosclerosis, the common pathological substrate underlying cardiovascular diseases, has been proposed to be an inflammatory disease [5]. Activated T-cells are present in human atherosclerotic plaques [6], and expression of pro-inflammatory cytokines, such as TNFα [7] and IL-1 [8], and chemokines, such as IL-8, RANTES, and MCP-1 [9,10] has been described. Cells
2 present in atherosclerotic lesions, including macrophages, endothelial cells, and smooth muscle cells, express MHC class II antigens, and CD4 + T cells and macrophages co-localize, mainly at the site of plaque rupture [11]. In parallel, clinical studies have highlighted the fact that elevated levels of C-reactive protein [12] and its main IL-6 [13], are associated with adverse prognosis in unstable angina patients. A complex array of mechanisms, including T cell activation, leukocyte extravasation, tissue factor expression, MMP expression and activation, as well induction of cytokines and chemokines, have been implicated in atherosclerosis, and many of these events are regulated by NFκB [14]. NfκB Activation in Atherosclerosis: The Evidence A number of studies have suggested that the NFκB pathway plays a key role in development of atherosclerosis. Many relevant stimuli have the potential to activate NFκB, including low density lipoprotein (LDL), infectious agents, and cytokines. For example, minimally oxidized LDL stimulate endothelial cells to produce NFκB-dependent chemokines and adhesion molecules [15]. Infectious agents such as Chlamydia pneumoniae, postulated to play a role in atherosclerosis, express molecules such as lipopolysaccharide (LPS), which activates NFκB in many cells, including endothelial cells and macrophages. Nuclear translocation of rela (p65) in the intima and media of human atherosclerotic plaques has been reported [16,17] and nuclear NFκB binding activity has been found in peripheral blood mononuclear cells [18] of patients with unstable angina. Furthermore, there is evidence for the importance of NFκB in development of atherosclerosis from animal models of disease. Activated NFκB was detected in coronary arteries of pigs fed a hypercholesterolemic diet [19] and in arterial smooth muscle cells of a rat balloon injury model [20]. In LDL receptor knock-out mice, expression of rela, IκBα, and IκBβ was considerably higher in a region of ascending aorta and arch predisposed to atherosclerotic lesion formation. However, nuclear translocation of rela was only found after initiation of an atherogenic diet, or after systemic injection of LPS, and even then, only in regions predisposed to atherosclerosis [21]. More recent studies have utilized LDL receptor knock-out mice with a macrophage-restricted deletion of IKK-2. Somewhat surprisingly, such animals showed an increased atherosclerotic lesion size [22]. To overcome some of the limitations of animal models, we have developed a short-term culture system of dissociated cells from human atherosclerotic tissue. These cells consist of a mixture of CD3 + lymphocytes, CD68 + macrophages, and smooth muscle cells. Using this shortterm culture system, we reported constitutive NFκB DNA-binding activity present in the nucleus of human atherosclerotic plaque cells. This activity was found to consist of p65, c-rel, and p50, but not relb and p52. Since relb and p52 are thought to be involved in the non-canonical pathway, these results suggest that it the canonical pathway of NFκB activation is induced in atherosclerosis [23]. NfκB Activation in Atherosclerosis: The Consequences Expression of NFκB in the atherosclerotic milieu is likely to have a number of potentially harmful consequences. For example, loss of fibrous cap integrity is likely to involve over-
3 expression of MMP. In human and rabbit smooth muscle cells, IL-1 activates NFκB to upregulate expression of MMP-1, -3, and -9 [24]. Oxidized LDL increases macrophage MMP-9, associated with increased nuclear binding of NFκB and AP-1 [25]. We have reported that human atherosclerotic plaque cells produce MMP-1, -3, and -9, as well as tissue inhibitor of MMP (TIMP)-1, and that expression of MMP-1, -3, and -9, but not TIMP-1, was strongly inhibited following adenovirally mediated over-expression of IκBα and a dominant-negative form of IKK- 2 [23]. Similarly, expression of tissue factor, the major initiator of the coagulation cascade, is regulated by NFκB [26]. In atherosclerotic plaque cells, tissue factor antigen and activity were inhibited following over-expression of IκBα and dominant-negative IKK-2, but not by dominant negative IKK-1 or NIK, supporting the concept that activation of the canonical pathway upregulates pro-thrombotic mediators involved in disease. Many of the cytokines and chemokines which have been detected in human atherosclerotic plaques are also regulated by NFκB. Over-expression of IκBα inhibits release of TNFα, IL-1, IL-6, and IL-8 in macrophages stimulated with LPS and CD40 ligand (CD40L) [27]. Interestingly, dominant negative IKK-2 adenovirus inhibited cytokine release in response to CD40L, but not LPS [27]. Secretion by macrophages of CXC chemokines in response to TNFα, but not LPS, was also suppressed following over-expression of IκBα, whereas expression of CC chemokines induced by either stimulus was reduced by IκBα [28]. These studies highlight the aspect that NFκB utilization depends on the cell type and stimulus. We have observed that expression of pro-inflammatory cytokines TNFα, IL-6, and IL-8, but not the anti-inflammatory cytokine IL-10, in human atherosclerotic plaque cells is NFκB-dependent and involves IKK-2, but not IKK-1 or NIK [23]. In contrast, deletion of IKK-2 in murine macrophages was associated with inhibition of both pro-inflammatory cytokines and IL-10, and was associated with increased atherosclerotic lesion size [22]. Differences between human and murine cells probably explain these discrepancies. NFκB is also a central player in cell survival, which is regulated, among others, by caspases and members of the Bcl-2 and inhibitors of apoptosis (IAP) families. To date, six IAP have been identified in humans, including HIAP-1 and -2, XIAP, and survivin. Induction of XIAP has been shown to be NFκB-dependent in TNFα-activated endothelial cells [29]. Moreover, the key angiogenic stimulus vascular endothelial growth factor (VEGF), which is expressed in atherosclerosis, upregulates Bcl-2, surviving, and XIAP in endothelial cells. We have shown that VEGF activates NFκB to induce Bcl-2 and survivin, via IKK-2. However, NFκB activation occurred without degradation of IκB, and is likely to involve tyrosine, rather than serine, phosphorylation of IκBα. Activation of NFκB in response to VEGF may be a key signaling event in regulating endothelial survival. In smooth muscle cells, proliferation induced by fibroblast growth factor has been shown to involve NFκB, and induction of HIAP-1 has been found to be NFκB-dependent [30]. Furthermore, adenoviral gene transfer of IκBα inhibited smooth muscle cell proliferation induced by cytokines [31]. Conclusion Atherosclerosis and its acute complications are a major cause of mortality and morbidity around the world. NFκB activation has been observed in animal models of and in human disease tissue. Our own data demonstrate for the first time that the canonical pathway of NFκB activation is activated in human atherosclerosis and results in selective upregulation of major pro-
4 inflammatory and pro-thrombotic mediators of the disease. Whether inhibition of the NFκB inhibition in atherosclerosis and its complications is a potential therapeutic option remains to be determined. Acknowledgements The Kennedy Institute of Rheumatology receives a core grant from the Arthritis Research Campaign. References 1. Greten FR, Karin M. The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 2004;206: Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 2004;3: Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000;18: Pomerantz JL, Baltimore D. Two pathways to NF-kappaB. Mol Cell 2002;10: Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105: Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989;135: Barath P, Fishbein MC, Cao J, et al. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol 1990;65: Moyer CF, Sajuthi D, Tulli H, et al. Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. Am J Pathol 1991;138: Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996;127: Yla-Herttuala S, Lipton BA, Rosenfeld ME, et al. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A 1991;88: Van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89: Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994;331: Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99: Monaco C, Paleolog E. Nuclear factor kappab: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res 2004;61: Frostegard J, Haegerstrand A, Gidlund M, et al. Biologically modified LDL increases the adhesive properties of endothelial cells. Atherosclerosis 1991;90: Brand K, Eisele T, Kreusel U, et al. Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 1997;17: Bourcier T, Sukhova G, Libby P. The nuclear factor kappa-b signaling pathway participates in dysregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. J Biol Chem 1997;272: Ritchie ME. Nuclear factor-kappab is selectively and markedly activated in humans with unstable angina pectoris. Circulation 1998;98: Wilson SH, Caplice NM, Simari RD, et al. Activated nuclear factor-kappab is present in the coronary vasculature in experimental hypercholesterolemia. Atherosclerosis 2000;148:23-30.
5 20. Landry DB, Couper LL, Bryant SR, et al. Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol 1997;151: Hajra L, Evans AI, Chen M, et al. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A 2000;97: Kanters E, Pasparakis M, Gijbels MJ, et al. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2003;112: Monaco C, Andreakos E, Kiriakidis S, et al. Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc Natl Acad Sci U S A 2004;101: Bond M, Chase AJ, Baker AH, et al. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc Res 2001;50: Xu XP, Meisel SR, Ong JM, et al. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation 1999;99: Wrighton CJ, Hofer-Warbinek R, Moll T, et al. Inhibition of endothelial cell activation by adenovirus-mediated expression of I kappa B alpha, an inhibitor of the transcription factor NFkappa B. J Exp Med 1996;183: Andreakos E, Smith C, Kiriakidis S, et al. Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy. Arthritis Rheum 2003;48: Ciesielski CJ, Andreakos E, Foxwell BM, et al. TNFalpha-induced macrophage chemokine secretion is more dependent on NF-kappaB expression than lipopolysaccharides-induced macrophage chemokine secretion. Eur J Immunol 2002;32: Stehlik C, de Martin R, Kumabashiri I, et al. Nuclear factor (NF)-kappaB-regulated X- chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med 1998;188: Beraud C, Henzel WJ, Baeuerle PA. Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-kappaB activation. Proc Natl Acad Sci U S A 1999;96: Zuckerbraun BS, McCloskey CA, Mahidhara RS, et al. Overexpression of mutated IkappaBalpha inhibits vascular smooth muscle cell proliferation and intimal hyperplasia formation. J Vasc Surg 2003;38: Please address correspondence to: Dr. Ewa Paleolog Kennedy Institute of Rheumatology & Division of Surgery, Anaesthetics and Intensive Care Faculty of Medicine, Imperial College Arthritis Research Campaign Building 1, Aspenlea Road London W6 8LH, UK Tel: Fax: e.paleolog@imperial.ac.uk
LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A 2 : EFFECTS OF LOW DENSITY LIPOPROTEIN APHERESIS
LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A 2 : EFFECTS OF LOW DENSITY LIPOPROTEIN APHERESIS Patrick M. Moriarty, M.D., FACP, Director, Atherosclerosis and LDL-Apheresis Center, University of Kansas Medical
More informationNFκB What is it and What s the deal with radicals?
The Virtual Free Radical School NFκB What is it and What s the deal with radicals? Emily Ho, Ph.D Linus Pauling Institute Scientist Department of Nutrition and Food Management Oregon State University 117
More informationN F-κB is a family of transcription factors central to
ii13 REPORT Is NF-κB a useful therapeutic target in rheumatoid arthritis? M Feldmann, E Andreakos, C Smith, J Bondeson, S Yoshimura, S Kiriakidis, C Monaco, C Gasparini, S Sacre, A Lundberg, E Paleolog,
More informationCardiovascular Division, Brigham and Women s Hospital, Harvard Medical School
Low Endothelial Shear Stress Upregulates Atherogenic and Inflammatory Genes Extremely Early in the Natural History of Coronary Artery Disease in Diabetic Hyperlipidemic Juvenile Swine Michail I. Papafaklis,
More informationThe aorta is an integral part of the cardiovascular system and should not be considered as just a conduit for blood supply from the heart to the
The aorta is an integral part of the cardiovascular system and should not be considered as just a conduit for blood supply from the heart to the limbs and major organs. A range of important pathologies
More informationCYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION
CYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION What is Cytokine? Secreted popypeptide (protein) involved in cell-to-cell signaling. Acts in paracrine or autocrine fashion through specific cellular receptors.
More informationMAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt.
MAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt. AUTOIMMUNE DISEASE RA SLE VASCULITIS RELAPSING POLYCHONDRITIS SS DM/PM SJOGREN S SYNDROME RHEUMATOID ARTHRITIS Classically immune mediated
More informationEndotoxin Induces Toll-Like Receptor 4 Expression in Vascular Cells: A Novel Mechanism Involved in Vascular Inflammation
Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Cells: A Novel Mechanism Involved in Vascular Inflammation Introduction Feng-Yen Lin, Ph.D. 1, and Shing-Jong Lin, M.D., PhD. 2, 1 Department
More informationEARLY INFLAMMATORY RESPONSES TO VASCULAR DEVICES
EARLY INFLAMMATORY RESPONSES TO VASCULAR DEVICES JAMES M. ANDERSON, MD, PhD DISTINGUISHED UNIVERSITY PROFESSOR DEPARTMENTS OF PATHOLOGY, MACROMOLECULAR SCIENCE, AND BIOMEDICAL ENGINEERING CASE WESTERN
More informationIL-17 in health and disease. March 2014 PSO13-C051n
IL-17 in health and disease March 2014 PSO13-C051n Originally Researchers Suggested That IL-12 and IL-4 drove Th Cell Differentiation Naïve CD4 + T cell Question: Which of these cell types is responsible
More informationPathology of Coronary Artery Disease
Pathology of Coronary Artery Disease Seth J. Kligerman, MD Pathology of Coronary Artery Disease Seth Kligerman, MD Assistant Professor Medical Director of MRI University of Maryland Department of Radiology
More informationThe NF- B/Rel family
The NF-κB/Rel family The NF-κB/Rel family A family of signal-responsive transcription factors rapid response som ikke requires proteinsyntese Involved in proinflammatory response: a first line of defense
More informationCytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Interleukins,
Cytokines http://highered.mcgraw-hill.com/sites/0072507470/student_view0/chapter22/animation the_immune_response.html Cytokines modulate the functional activities of individual cells and tissues both under
More informationVulnerable Plaque. Atherothrombosis
Vulnerable Plaque Nuove acquisizioni sull'aterosclerosi: placca vulnerabile Marina Camera Dip. Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano & Laboratorio di Biologia Cellulare
More informationNewly Recognized Components of the Innate Immune System
Newly Recognized Components of the Innate Immune System NOD Proteins: Intracellular Peptidoglycan Sensors NOD-1 NOD-2 Nod Protein LRR; Ligand Recognition CARD RICK I-κB p50 p65 NF-κB Polymorphisms in Nod-2
More informationMaterials and Methods
Short term hyperthermia prevents activation of proinflammatory genes in type B synoviocytes by blocking the activation of the transcription factor NF-κB Marica Markovic Institute of Medical Biochemistry,
More informationCIC Edizioni Internazionali. Cardio-metabolic comorbidities in rheumatoid arthritis and SLE. Review. 120 Clinical Dermatology 2013; 1 (2):
Review Cardio-metabolic comorbidities in rheumatoid arthritis and SLE Andrea Doria Division of Rheumatology University of Padua, Italy Address for correspondence: Division of Rheumatology University of
More informationDyslipidemia Endothelial dysfunction Free radicals Immunologic
ATHEROSCLEROSIS Hossein Mehrani Professor of Clinical Biochemistry Definition Atherosclerosis: Is a chronic inflammatory process characterized by plaque formation within the vessel wall of arteries and
More informationBasic Mechanisms of Atherosclerosis and Plaque Rupture: Clinical Implications
12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 KEYNOTE ADDRESS Basic Mechanisms of Atherosclerosis and Plaque Rupture: Clinical Implications Ira Tabas, M.D., Ph.D. Richard J.
More informationArteriosclerosis & Atherosclerosis
Arteriosclerosis & Atherosclerosis Arteriosclerosis = hardening of arteries = arterial wall thickening + loss of elasticity 3 types: -Arteriolosclerosis -Monckeberg medial sclerosis -Atherosclerosis Arteriosclerosis,
More informationIntrinsic cellular defenses against virus infection
Intrinsic cellular defenses against virus infection Detection of virus infection Host cell response to virus infection Interferons: structure and synthesis Induction of antiviral activity Viral defenses
More informationThe 10 th International & 15 th National Congress on Quality Improvement in Clinical Laboratories
The 10 th International & 15 th National Congress on Quality Improvement in Clinical Laboratories Cardiac biomarkers in atherosclerosis Najma Asadi MD-APCP Ross and Colleagues in 1973: Response to Injury
More informationNTD Vaccine Design Toolkit and Training Workshop Providence, RI January 05, 2011 Cytokines Leslie P. Cousens, PhD EpiVax, Inc.
NTD Vaccine Design Toolkit and Training Workshop Providence, RI January 05, 2011 Cytokines Leslie P. Cousens, PhD EpiVax, Inc. Cytokines Properties of Cytokines Cytokines are proteins with specific roles
More informationTHE CARDIOVASCULAR INFLAMMATORY CONTINUUM DR AB MAHARAJ
THE CARDIOVASCULAR INFLAMMATORY CONTINUUM DR AB MAHARAJ Disclosures: On National Advisory Boards of: (1) Pfizer Pharmaceuticals (2) MSD (3) Roche Pharmaceuticals (4) Abbott International: AfME Rheumatology
More informationCytokines, adhesion molecules and apoptosis markers. A comprehensive product line for human and veterinary ELISAs
Cytokines, adhesion molecules and apoptosis markers A comprehensive product line for human and veterinary ELISAs IBL International s cytokine product line... is extremely comprehensive. The assays are
More informationROLE OF INFLAMMATION IN HYPERTENSION. Dr Barasa FA Physician Cardiologist Eldoret
ROLE OF INFLAMMATION IN HYPERTENSION Dr Barasa FA Physician Cardiologist Eldoret Outline Inflammation in CVDs the evidence Basic Science in Cardiovascular inflammation: The Main players Inflammation as
More informationObesity is related to a higher inflammatory responsive state of circulating cells after stimulation of toll like receptor 2 and 4.
Toll Like Receptor Response and traditional risk factors for atherosclerosis: Obesity is related to a higher inflammatory responsive state of circulating cells after stimulation of toll like receptor 2
More informationSubject Index. Bcl-2, apoptosis regulation Bone marrow, polymorphonuclear neutrophil release 24, 26
Subject Index A1, apoptosis regulation 217, 218 Adaptive immunity, polymorphonuclear neutrophil role 31 33 Angiogenesis cancer 178 endometrium remodeling 172 HIV Tat induction mechanism 176 inflammatory
More informationVirchow s Hypothesis lymphorecticular infiltration of cancer reflected the origin of cancer at sites of inflammation
Virchow s Hypothesis 1863 lymphorecticular infiltration of cancer reflected the origin of cancer at sites of inflammation Barrett s esophagus/ Esophageal adenocarcinoma PSC / Cholangiocarcinoma Viral hepatitis
More informationSerial changes in plasma levels of cytokines in patients with coronary artery disease
ORIGINAL RESEARCH Serial changes in plasma levels of cytokines in patients with coronary artery disease Roberto H Heinisch 1 Carlos R Zanetti 1 Fabiano Comin 1 Juliano L Fernandes 2 José A Ramires 2 Carlos
More informationrenoprotection therapy goals 208, 209
Subject Index Aldosterone, plasminogen activator inhibitor-1 induction 163, 164, 168 Aminopeptidases angiotensin II processing 64 66, 214 diabetic expression 214, 215 Angiotensin I intrarenal compartmentalization
More informationAnimal viruses as model systems to study activation of gene networks.
Discovery and assessment of new target sites for anti-hiv therapies: an approach to utilize genome wide gene expression changes and computational models. Sanjive Qazi. Introduction. Animal viruses as model
More informationStewart et al. CD36 ligands promote sterile inflammation through assembly of a TLR 4 and 6 heterodimer
NFκB (fold induction) Stewart et al. ligands promote sterile inflammation through assembly of a TLR 4 and 6 heterodimer a. mrna (fold induction) 5 4 3 2 1 LDL oxldl Gro1a MIP-2 RANTES mrna (fold induction)
More informationImmune Cells in Atherosclerosis Regulatory vs Inflammatory T cells Göran K Hansson
Immune Cells in Atherosclerosis Regulatory vs Inflammatory T cells Göran K Hansson Center for Molecular Medicine Karolinska Institute Stockholm, Sweden DECLARATION OF CONFLICT OF INTEREST Goran Hansson
More informationAutoimmune Diseases. Betsy Kirchner CNP The Cleveland Clinic
Autoimmune Diseases Betsy Kirchner CNP The Cleveland Clinic Disclosures (financial) No relevant disclosures Learning Objectives Explain the pathophysiology of autoimmune disease Discuss safe administration
More informationPotential Role of Sphingosine 1-Phosphate in the. Pathogenesis of Rheumatoid Arthritis
Potential Role of Sphingosine 1-Phosphate in the Pathogenesis of Rheumatoid Arthritis COMMENTARY for Zhao, C., Fernandes, M.J., Turgeon, M., Tancrede, S., Di Battista, J., Poubelle, P.E. and Bourgoin,
More informationAnnals of RSCB Vol. XVI, Issue 1
THE STUDY OF PROTHROBOTIC STATE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASES Oana Bădulescu 1, Codruţa Bădescu 2, Manuela Ciocoiu 1, Magda Bădescu 1 1 DEPARTMENT OF PATHOPHYSIOLOGY;
More informationFollicular Lymphoma. ced3 APOPTOSIS. *In the nematode Caenorhabditis elegans 131 of the organism's 1031 cells die during development.
Harvard-MIT Division of Health Sciences and Technology HST.176: Cellular and Molecular Immunology Course Director: Dr. Shiv Pillai Follicular Lymphoma 1. Characterized by t(14:18) translocation 2. Ig heavy
More informationProteomics to identify novel biomarkers and therapeutic targets in cardiovascular disease
Proteomics to identify novel biomarkers and therapeutic targets in cardiovascular disease Markus Kubicek Laboratorios de Biologia Vascular y Proteínómica Estructural, Instituto de Biomedicina de Valencia
More informationACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS. Choompone Sakonwasun, MD (Hons), FRCPT
ACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS Choompone Sakonwasun, MD (Hons), FRCPT Types of Adaptive Immunity Types of T Cell-mediated Immune Reactions CTLs = cytotoxic T lymphocytes
More informationInnate Immunity. Chapter 3. Connection Between Innate and Adaptive Immunity. Know Differences and Provide Examples. Antimicrobial peptide psoriasin
Chapter Know Differences and Provide Examples Innate Immunity kin and Epithelial Barriers Antimicrobial peptide psoriasin -Activity against Gram (-) E. coli Connection Between Innate and Adaptive Immunity
More informationSubclinical inflammation and peripheral artery disease. Luigi M Biasucci, M.D. Institute of Cardiology Catholic University Rome, ITALY
Subclinical inflammation and peripheral artery disease Luigi M Biasucci, M.D. Institute of Cardiology Catholic University Rome, ITALY ESC Congress 2010 Conflict of interest Research grants:sanofi-aventis,
More informationImmune Regulation and Tolerance
Immune Regulation and Tolerance Immunoregulation: A balance between activation and suppression of effector cells to achieve an efficient immune response without damaging the host. Activation (immunity)
More informationThematic review series: The Immune System and Atherogenesis
thematic review Thematic review series: The Immune System and Atherogenesis Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? Alan Chait, 1 Chang Yeop Han, John
More informationFocal Infection Theory
Paradigm Shift Focal Infection Theory 1900, British physician William Hunter first developed the idea that oral microorganisms were responsible for a wide range of systemic conditions that were not easily
More informationCan seal oil contribute to better human health?
Can seal oil contribute to better human health? Bjarne Østerud and Edel O. Elvevoll, Faculty of Medicine and NFH, University of Tromsø E-mail: bjarne@fagmed. Historical background Old food lore of seafood
More informationBasis of Immunology and
Basis of Immunology and Immunophysiopathology of Infectious Diseases Jointly organized by Institut Pasteur in Ho Chi Minh City and Institut Pasteur with kind support from ANRS & Université Pierre et Marie
More informationRole of Inflammatory and Progenitor Cells in Pulmonary Vascular Remodeling: Potential Role for Targeted Therapies. Traditional Hypothesis Stress
3/1/212 Role of Inflammatory and Progenitor Cells in Pulmonary Vascular Remodeling: Potential Role for Targeted Therapies K.R. Stenmark University of Colorado Denver, CO 845 Prominent Fibroproliferative
More informationalveolar macrophages (AMs) after 24 hours of in vitro culture in complete medium
Online Supplement for: NF-κB ACTIVATION IN ALVEOLAR MACROPHAGES REQUIRES IκB KINASE-β, BUT NOT NF-κB INDUCING KINASE Supershift and Competition Assays for NF-κB Competition and supershift assays were performed
More informationImmunology lecture: 14. Cytokines: Main source: Fibroblast, but actually it can be produced by other types of cells
Immunology lecture: 14 Cytokines: 1)Interferons"IFN" : 2 types Type 1 : IFN-Alpha : Main source: Macrophages IFN-Beta: Main source: Fibroblast, but actually it can be produced by other types of cells **There
More informationAdipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University
Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides,
More informationNEUTROPHIL-PLATELET INTERACTION
NEUTROPHIL-PLATELET INTERACTION Johnny Nijm, MD; PhD Specialist in Internal medicine, Cardiology & Clinical Physiology Department of Medicine Diagnostic, Division of Clinical Physiology, County Hospital
More informationAtherosclerosis, inflammation and leukotrienes
Review. Ingvill Ellertsen, Marcelo H. Petri, Magnus Bäck Atherosclerosis, inflammation and leukotrienes Michael Quarterly 2011;8:514 22. Atherosclerosis, which is a chronic inflammatory disease that leads
More informationImmunological Aspect of Ozone in Rheumatic Diseases
Immunological Aspect of Ozone in Rheumatic Diseases Prof. Dr. med. Z. Fahmy Chief Consulting Rheumatologist Augusta Clinic for Rheumatic Diseases And Rehabilitation Bad Kreuznach Germany Rheumatoid arthritis
More informationINVESTIGATING THE ROLE OF IKKε. CANCER-ASSOCIATED NF-κB ACTIVITY. Mezher Adli. Chapel Hill 2007
INVESTIGATING THE ROLE OF IKKε (EPSILON) IN CANCER-ASSOCIATED NF-κB ACTIVITY Mezher Adli A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment
More informationUntil recently, atherosclerosis was
Heart 2000;83:247 252 CORONARY DISEASE Atherogenesis: current understanding of the causes of atheroma Peter L Weissberg School of Clinical Medicine, University of Cambridge, Cambridge, UK Correspondence
More informationPATIENTS AND METHODS:
BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by erosive synovitis that involves peripheral joints and implicates an important influence in the quality
More informationT Cell Effector Mechanisms I: B cell Help & DTH
T Cell Effector Mechanisms I: B cell Help & DTH Ned Braunstein, MD The Major T Cell Subsets p56 lck + T cells γ δ ε ζ ζ p56 lck CD8+ T cells γ δ ε ζ ζ Cα Cβ Vα Vβ CD3 CD8 Cα Cβ Vα Vβ CD3 MHC II peptide
More information12/10/2009. Department of Pathology, Case Western Reserve University. Mucosal Cytokine Network in IBD
Cytokine-Mediated Inflammation in IBD Theresa T. Pizarro Department of Pathology, Case Western Reserve University Mucosal Cytokine Network in IBD Andoh, et al., 2008 1 Interleukin-1 (IL-1) Family Cytokine
More informationPATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROMES
PATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROMES Brian R. Holroyd, MD, FACEP, FRCPC Professor and Director, Division of Emergency Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,
More informationTranscription factors in airway diseases
& 2006 USCAP, Inc All rights reserved 0023-6837/06 $30.00 www.laboratoryinvestigation.org Peter J Barnes Section of airway diseases, National Heart & Lung Institute, Imperial College, London, UK Transcription
More informationNormal GC initiation then collapse; normal mutation and 10. Constitutive signalling leads to spontaneous GC in PP, even BCR -/- 19
S1 Genetic modifications affecting germinal-centre formation and function Gene Compartment GC Phenotype Ref LTα, LTβ, TNF, Organ Disorganized lymphoid architecture in spleens; poor 1 TNFRI, LTβR architecture
More informationCrosstalk between Adiponectin and IGF-IR in breast cancer. Prof. Young Jin Suh Department of Surgery The Catholic University of Korea
Crosstalk between Adiponectin and IGF-IR in breast cancer Prof. Young Jin Suh Department of Surgery The Catholic University of Korea Obesity Chronic, multifactorial disorder Hypertrophy and hyperplasia
More informationTracking a Killer Molecule
Tracking a Killer Molecule Mercodia Oxidized LDL ELISA www.mercodia.com Mercodia Oxidized LDL ELISA products Product Catalog No Kit size Oxidized LDL ELISA 10-1143-01 96 wells Oxidized LDL competitive
More informationAnti-inflammatory properties of SM04690, a small molecule inhibitor of the Wnt pathway as a potential treatment for knee osteoarthritis
Anti-inflammatory properties of SM04690, a small molecule inhibitor of the Wnt pathway as a potential treatment for knee osteoarthritis V. Deshmukh 1, T. Seo 1, C. Swearingen 1, Y. Yazici 1 1 Samumed,
More informationWe are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists. International authors and editors
We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists 3,900 116,000 120M Open access books available International authors and editors Downloads Our
More informationChapter 13: Cytokines
Chapter 13: Cytokines Definition: secreted, low-molecular-weight proteins that regulate the nature, intensity and duration of the immune response by exerting a variety of effects on lymphocytes and/or
More informationI t is becoming increasingly clear that inflammation plays a
25 CARDIOVASCULAR MEDICINE Raised concentrations of macrophage colony stimulating factor in severe unstable angina beyond the acute phase are strongly predictive of long term outcome L S Rallidis, M G
More informationInflammation and and Heart Heart Disease in Women Inflammation and Heart Disease
Inflammation and Heart Disease in Women Inflammation and Heart Disease What is the link between een inflammation and atherosclerotic disease? What is the role of biomarkers in predicting cardiovascular
More informationPROTEÓMICA y SAF. Maria Josė Cuadrado Lupus Research Unit St. Thomas Hospital London UK
PROTEÓMICA y SAF Maria Josė Cuadrado Lupus Research Unit St. Thomas Hospital London UK Aknowledgments Chary López-Pedrera Angeles Aguirre Francisco Velasco Hospital Reina Sofia, Córdoba, España Laura Bertolaccini
More informationChapter 11. B cell generation, Activation, and Differentiation. Pro-B cells. - B cells mature in the bone marrow.
Chapter B cell generation, Activation, and Differentiation - B cells mature in the bone marrow. - B cells proceed through a number of distinct maturational stages: ) Pro-B cell ) Pre-B cell ) Immature
More informationGlossary For TheFatNurse s For All Ages Series Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Apolipoprotein
More informationVIII Curso Internacional del PIRRECV. Some molecular mechanisms of cancer
VIII Curso Internacional del PIRRECV Some molecular mechanisms of cancer Laboratorio de Comunicaciones Celulares, Centro FONDAP Estudios Moleculares de la Celula (CEMC), ICBM, Facultad de Medicina, Universidad
More informationInvited Review. Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular diseases
Histol Histopathol (2000) 15: 557-571 Histology and Histopathology Cellular and Molecular Biology Invited Review Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular
More informationThe death receptors: signaling and modulation
The death receptors: signaling and modulation 1 1 The extrinsic cell death pathway 2 Nat Rev Drug Discov. 2008 Dec;7(12):1001-12. 2 Death receptors Belong to the tumor necrosis factor (TNF) receptor gene
More informationRoles of Flow Mechanics in Vascular Cell Biology in Health and Disease
Roles of Flow Mechanics in Vascular Cell Biology in Health and Disease Shu Chien Dept. of Bioengineering & Medicine UC, San Diego Presented by Ming-Shaung Ju Dept. of Mech. Eng., NCKU, Tainan Background
More informationT cell maturation. T-cell Maturation. What allows T cell maturation?
T-cell Maturation What allows T cell maturation? Direct contact with thymic epithelial cells Influence of thymic hormones Growth factors (cytokines, CSF) T cell maturation T cell progenitor DN DP SP 2ry
More informationNovel function of NADPH oxidase in atherosclerosis. Yun Soo Bae Department of Life Science Ewha Womans University
Novel function of NADPH oxidase in atherosclerosis Yun Soo Bae Department of Life Science Ewha Womans University Recent understanding of ROS: act as second messengers e e Catalase/peroxidase O 2 H 2 O
More information9607 Dr. Perry Road Suite 103. Ijamsville, MD Tel: (301) Fax: (301) Ultrasensitive Samoa Human IL-33 Immunoassay
AssayGate, Inc. 9607 Dr. Perry Road Suite 103. Ijamsville, MD 21754. Tel: (301)874-0988. Fax: (301)560-8288. Ultrasensitive Samoa Human IL-33 Immunoassay INTRODUCTION Interleukin-33 (IL-33), a cytokine
More informationUvA-DARE (Digital Academic Repository) NF-kappa B: a key role in inflammatory diseases Tak, P.P.; Firestein, G.S.
UvA-DARE (Digital Academic Repository) NF-kappa B: a key role in inflammatory diseases Tak, P.P.; Firestein, G.S. Published in: The journal of clinical investigation DOI: 10.1172/JCI11830 Link to publication
More informationT-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:
Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,
More informationT-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:
Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,
More informationGeneration of post-germinal centre myeloma plasma B cell.
Generation of post-germinal centre myeloma. DNA DAMAGE CXCR4 Homing to Lytic lesion activation CD38 CD138 CD56 Phenotypic markers Naive Secondary lymphoid organ Multiple myeloma is a malignancy of s caused
More informationChapter 11. B cell generation, Activation, and Differentiation. Pro-B cells. - B cells mature in the bone marrow.
Chapter B cell generation, Activation, and Differentiation - B cells mature in the bone marrow. - B cells proceed through a number of distinct maturational stages: ) Pro-B cell ) Pre-B cell ) Immature
More informationACTIVATION OF T LYMPHOCYTES AND CELL MEDIATED IMMUNITY
ACTIVATION OF T LYMPHOCYTES AND CELL MEDIATED IMMUNITY The recognition of specific antigen by naïve T cell induces its own activation and effector phases. T helper cells recognize peptide antigens through
More informationHIV AND INFLAMMATION: A NEW THREAT
HIV AND INFLAMMATION: A NEW THREAT KAP ANNUAL SCIENTIFIC CONFERENC MAY 2013 DR JOSEPH ALUOCH FRCP,EBS Basic Components of the Immune System Immunology: cells and tissues involved in recognizing and attacking
More information?Who binds to it. ? Who binds these inflammatory proteins RAGE SUGAR-FREE GLYCOBIOLOGY INFLAMMATION. BASIC SCIENCE?sugar chain structure
SUGAR-FREE GLYCOBIOLOGY BASIC SCIENCE?sugar chain structure Unusual Sugar Chain It -- is a carboxylate Make lots of It Make an It antibody Inflammatory proteins?who binds to it? Who binds these inflammatory
More informationInflammation in the clinic
Inflammation in the clinic Stephen T. Holgate MRC Clinical Professor of Immunopharmacology ILSI Europe Workshop, Seville, May 14-15 2012 The immune system acts in four general ways to ensure host defence
More informationThe Study of Endothelial Function in CKD and ESRD
The Study of Endothelial Function in CKD and ESRD Endothelial Diversity in the Human Body Aird WC. Circ Res 2007 Endothelial Diversity in the Human Body The endothelium should be viewed for what it is:
More informationInnate Immunity in Atherosclerosis
Innate Immunity in Atherosclerosis Peter Libby Brigham & Women s Hospital Harvard Medical School IAS Amsterdam May 26, 2015 ACS Stable demand angina Characteristics of Atherosclerotic Plaques Associated
More informationPathology of the Vulnerable Plaque
Journal of the American College of Cardiology Vol. 47, No. 8 Suppl C 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2005.10.065
More informationLeptin deficiency suppresses progression of atherosclerosis in apoe-deficient mice
Leptin deficiency suppresses progression of atherosclerosis in apoe-deficient mice Atherosclerosis, 2007 Chiba T, Shinozaki S, Nakazawa T, et al. Present by Sudaporn Pummoung Apolipoprotein E (apoe( apoe)
More informationInterleukin-6; pathogenesis and treatment of autoimmune inflammatory diseases
54 Review Article Interleukin-6; pathogenesis and treatment of autoimmune inflammatory diseases Toshio Tanaka 1, 2), Masashi Narazaki 3), Kazuya Masuda 4) and Tadamitsu Kishimoto 4, ) 1) Department of
More informationRole of apolipoprotein B-containing lipoproteins in the development of atherosclerosis Jan Borén MD, PhD
Role of apolipoprotein B-containing lipoproteins in the development of atherosclerosis Jan Borén MD, PhD Our laboratory focuses on the role of apolipoprotein (apo) B- containing lipoproteins in normal
More informationPathophysiology of Lipid Disorders
Pathophysiology of Lipid Disorders Henry Ginsberg, M.D. Division of Preventive Medicine and Nutrition CHD in the United States CHD is the single largest killer of men and women 12 million have history
More informationPre-made Reporter Lentivirus for NF-κB Signal Pathway
Pre-made Reporter for NF-κB Signal Pathway Cat# Product Name Amounts LVP965-P or: LVP965-P-PBS NFKB-GFP (Puro) LVP966-P or: LVP966-P-PBS NFKB-RFP (Puro) LVP967-P or: LVP967-P-PBS NFKB-Luc (Puro) LVP968-P
More informationAttribution: University of Michigan Medical School, Department of Microbiology and Immunology
Attribution: University of Michigan Medical School, Department of Microbiology and Immunology License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution
More informationCytokines (II) Dr. Aws Alshamsan Department of Pharmaceu5cs Office: AA87 Tel:
Cytokines (II) Dr. Aws Alshamsan Department of Pharmaceu5cs Office: AA87 Tel: 4677363 aalshamsan@ksu.edu.sa Learning Objectives By the end of this lecture you will be able to: 1 Understand the physiological
More information10/17/16. Assessing cardiovascular risk through use of inflammation testing
Assessing cardiovascular risk through use of inflammation testing Anthony L. Lyssy, DO Medical Director and Managing Partner Diamond Physicians Dallas, TX Response to Injury Hypothesis Injury Response
More informationPost-translational modifications of proteins in gene regulation under hypoxic conditions
203 Review Article Post-translational modifications of proteins in gene regulation under hypoxic conditions 1, 2) Olga S. Safronova 1) Department of Cellular Physiological Chemistry, Tokyo Medical and
More information