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4 results on '"Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings]"'

1. Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis

Author

Alejandra M. Patiño-Trives, Chary López-Pedrera, José Luis Marenco, Rafaela Ortega-Castro, Carlos Perez-Sanchez, M. Romero-Gómez, Iván Arias de la Rosa, Alejandro Escudero-Contreras, Eduardo Collantes-Estevez, Natalia Mena-Vázquez, Nuria Barbarroja, Pilar Font, Antonio Fernández-Nebro, J.J. Pérez-Venegas, Desiree Ruiz-Vilchez, Carmen Dominguez, M. D. C. Abalos-Aguilera, C.M. Romero-Barco, Juan Antonio Marin-Sanz, M. Angeles Aguirre, Carlos Rodriguez-Escalera, Mª Dolores Ruiz-Montesinos, Julia Uceda-Montañez, María Luque-Tévar, Mª Dolores Toledo-Coello, Clementina López-Medina, [Luque-Tévar,M, Perez-Sanchez,C, Patiño-Trives,AM, Barbarroja,N, Arias de la Rosa,I, Abalos-Aguilera,MC, Marin-Sanz,JA, Ruiz-Vilchez,D, Ortega-Castro,R, Font,P, Lopez-Medina,C, Romero-Gomez,M, Aguirre,MA, Escudero-Contreras,A, Collantes-Estevez,E, Lopez-Pedrera,C] Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofia, Universidad de Cordoba, Córdoba, Spain. [Rodriguez-Escalera,C] Hospital Universitario de Jaen, Jaén, Spain. [Perez-Venegas,J, Ruiz-Montesinos,MD, Dominguez,C] Hospital Universitario Virgen Macarena, Sevilla, Spain. [Romero-Barco,C] Hospital Clínico Universitario, Malaga, Spain. [Fernandez-Nebro,A, Mena-Vazquez,N] Hospital Regional Universitario de Malaga, Malaga, Spain. [Marenco,JL, Uceda-Montañez,J] Hospital Universitario Virgen de Valme, Sevilla, Spain. [Toledo-Coello,MD] Hospital Universitario de Jerez de la Frontera, Cádiz, Spain., and This study was supported by grants from the Instituto de Salud Carlos III (PI18/00837), cofinanciado por el Fondo Europeo de Desarrollo Regional de la Unión Europea Una manera de hacer Europa, Spain, the Spanish Inflammatory and Rheumatic Diseases Network (RIER), Instituto de Salud Carlos III (RD16/0012/0015) and the Andalusian Regional Health System (ref. PI-0285-2017). CL-P was supported by a contract from the Spanish Junta de Andalucía (Nicolas Monardes program).

Subjects
Male, 0301 basic medicine, Oncology, rheumatoid arthritis, Longitudinal study, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], efficacy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [Medical Subject Headings], Logistic regression, Extracellular Traps, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Arthritis, Rheumatoid, 0302 clinical medicine, Cluster Analysis, Immunology and Allergy, Longitudinal Studies, Prospective Studies, Computational analysis, Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress [Medical Subject Headings], Original Research, MicroARNs, Estrés oxidativo, Anti-TNF agents, Middle Aged, Phenotype, Aprendizaje automático, microRNAs, Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, Rheumatoid [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Sensitivity and Specificity::Predictive Value of Tests [Medical Subject Headings], Treatment Outcome, machine learning, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models [Medical Subject Headings], Eficacia, Antirheumatic Agents, Rheumatoid arthritis, Cohort, Female, Tumor necrosis factor alpha, anti-TNF agents, medicine.symptom, Fenotipo, Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings], Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Phenomena and Processes::Mathematical Concepts::Algorithms [Medical Subject Headings], Efficacy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Immunology, Check Tags::Male [Medical Subject Headings], Inflammation, Artritis reumatoide, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Cluster Analysis [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents [Medical Subject Headings], NEtosis, 03 medical and health sciences, Predictive Value of Tests, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies [Medical Subject Headings], Internal medicine, Machine learning, medicine, Humans, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], 030203 arthritis & rheumatology, Inflamación, Predictors, business.industry, Inhibidores del factor de necrosis tumoral, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Area Under Curve [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], medicine.disease, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs [Medical Subject Headings], MicroRNAs, Oxidative Stress, Biomarcadores, predictors, 030104 developmental biology, Check Tags::Female [Medical Subject Headings], Oxidative stress, inflammation, Tumor Necrosis Factor Inhibitors, business, lcsh:RC581-607, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Biomarkers
Abstract

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients.Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions.Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort.Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.

Published
2021
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2. Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study

Author

Miguel Ferrer, Ann W. Morgan, Beatriz Joven, John D. Isaacs, Theologia Sarafidou, Enrique Raya, Rafael Cáliz, Javier Narváez, Ariana Montes, Ana Márquez, C. Magro, Javier Martín, F. Navarro-Sarabia, Moreira Vf, María del Carmen Ordóñez, Lara Valor, Alejandro Balsa, Antonio Fernández-Nebro, Juan José Alegre-Sancho, Arturo Rodríguez de la Serna, Anne Barton, Rosa Garcia-Portales, Manuel J. Moreno-Ramos, Antonio Gonzalez, Anthony G. Wilson, Francisco J. Blanco, Patricia Carreira, Yiannis Vasilopoulos, Juan J. Gomez-Reino, Darren Plant, Berta Magallares, Juan D. Cañete, Eva Perez-Pampin, Dora Pascual-Salcedo, Universitat de Barcelona, Instituto de Salud Carlos III, European Commission, [Montes,A, Perez-Pampin,E] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. [Navarro-Sarabia, F, Moreira,V] Rheumatology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Rodríguez de la Serna,A, Magallares,B] Rheumatology Unit, Hospital Santa Creu e San Pau, Barcelona, Spain. [Vasilopoulos,Y, Sarafidou,T] Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece. [Fernández-Nebro,A, Ordóñez,MC] Servicio de Reumatología, HRU Carlos Haya, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Narváez,J] Department of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain. [Cañete,Jd] Rheumatology Unit, Hospital Clinic, Barcelona, Spain. [Marquez,A] Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. [Pascual-Salcedo,D] Department of Immunology, Instituto de Investigación Hospital Universitario La Paz, Hospital La Paz, Madrid, Spain. [Joven,B, Carreira,P] Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain. [Moreno-Ramos,MJ] Department of Rheumatology, Hospital Virgen de la Arrixaca, Murcia, Spain. [Caliz,R, Ferrer,NA] Rheumatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Garcia-Portales,R] Department of Rheumatology, Hospital Virgen de la Victoria, Málaga, Spain. [Blanco,FJ] Rheumatology Department, Instituto de Investigacion Biomedica-Complejo Hospitalario Universitario A Coruna, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. [Magro,C, Raya,E] Department of Rheumatology, Hospital Clínico San Cecilio, Granada, Spain. [Valor,L] Rheumatology Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Alegre-Sancho,JJ] Department of Rheumatology, Hospital Doctor Peset, Valencia, Spain. [Balsa,A] Department of Rheumatology, Instituto de Investigación Hospital Universitario La Paz, Hospital Universitario La Paz, Madrid, Spain.[Martin,J] Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. [Plant,D] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. [Isaacs,J] Musculoskeletal Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, Newcastle, UK. [Morgan,AW] Leeds Institute of Rheumatic and Musculoskeletal Medicine, St. James's University Hospital, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK. [Barton,A] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Arthritis Research UK-Centre for Genetics and Genomics, The University of Manchester, Manchester, UK. [Wilson,AG] University College Dublin, Dublin, Ireland. [Gómez-Reino,JJ] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. [Gonzalez,A] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Laboratorio Investigacion 10, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain., Funding was provided by grants PI11/01048, PI12/01909 and by RETICS Program, RD08/0075/0019 and RD12/0009/0008 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union, UAM. Departamento de Medicina, and Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)

Subjects
Male, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], Immunoglobulin G, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Arthritis, Rheumatoid, Immunology and Allergy, Single nucleotide, skin and connective tissue diseases, biology, IgG1 allotype, Drugs, Enfermedades reumáticas, Middle Aged, Allotype, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Monokines::Tumor Necrosis Factor-alpha [Medical Subject Headings], Articulaciones, Treatment Outcome, Estudi de casos, Rheumatoid arthritis, Diseases::Musculoskeletal Diseases::Rheumatic Diseases [Medical Subject Headings], Arthritis rheumatoid, Antirheumatic Agents, Teràpia genètica, Tumor necrosis factor alpha, Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Antibody, Medicaments, medicine.drug, Research Article, Adult, musculoskeletal diseases, medicine.medical_specialty, Genotype, Medicina, Anatomy::Musculoskeletal System::Skeleton::Joints [Medical Subject Headings], Immunology, Molecular Sequence Data, Artritis reumatoide, Polymorphism, Single Nucleotide, Gene therapy, Rheumatology, Internal medicine, Diseases::Musculoskeletal Diseases::Joint Diseases::Arthritis::Arthritis, Rheumatoid [Medical Subject Headings], medicine, Adalimumab, Humans, Polymorphism, Immunoglobulin Allotypes, Base Sequence, business.industry, Tumor Necrosis Factor-alpha, medicine.disease, Infliximab, Factor de necrosis tumoral alfa, Treatment, biology.protein, Case studies, business, Genotipo
Abstract

Montes, Ariana et al., [Introduction] We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA)., [Methods] The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria., [Results] An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication., [Conclusions] Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA., Funding was provided by grants PI11/01048, PI12/01909 and by RETICS Program, RD08/0075/0019 and RD12/0009/0008 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union.

Published
2015

3. The rise of soluble TWEAK levels in severely obese subjects after bariatric surgery may affect adipocyte-cytokine production induced by TNFα

Author

Joan Vendrell, Eduardo García-Fuentes, Antonio Garcia España, Matilde R. Chacón, Sonia Fernández-Veledo, María del Mar González Rodríguez, Lourdes Garrifo-Sanchez, Francisco J. Tinahones, Ana Vázquez-Carballo, Elsa Maymó-Masip, [Maymó-Masip,E, Fernández-Veledo,S, Vázquez-Carballo,A, Garrifo-Sánchez,L, Vendrell,J, Chacón,MR] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Madrid, Spain. [Maymó-Masip,E, García-España,A, Chacón,MR] Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Madrid, Spain. [Vázquez-Carballo,A] Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, Madrid, Spain. [Tinahones,FJ, García-Fuentes,E, Rodríguez,M del M] Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad/Nutrición, Hospital Virgen de la Victoria, Málaga, Spain. [Tinahones,FJ] Department of Obesity and Nutrition, Hospital Virgen de la Victoria, Málaga, Spain. [García-Fuentes,E] Servicio de Endocrinología y Nutrición, Hospital Regional, Universitario Carlos Haya, Málaga, Spain. [García-Fuentes,E] Instituto de Investigaciones Biomédicas de Málaga, Spain. [Rodríguez,M del M] Department of Diabetes, Endocrinology, and Nutrition, Institut d'Investigació Biomèdica de Girona, Spain., and This work was supported by projects from the Fondo de Investigación Sanitaria: Grant PI 11/00049 (to M.R.CH), Grant PI08/0733 (to M.R.C.), Grant SAF2012-36186 (to S.F.-V.) and from the Project Consolider Ingenio Grant CSD-2010-00065 (to A.G.-E.). S.F.-V. acknowledges support from the 'Miguel Servet' tenure track program (Grant CP10/00438) from the Fondo de Investigación Sanitaria. All support from the Fondo de Investigación Sanitaria are cofinanced by the European Regional Development Fund. A.G.-E., M.R.C., and E.G.-F. are supported by the Research Stabilization Programme of the Instituto de Salud Carlos III. M.R.C. and A.G.-E. are also cofinanced by Institut Català de Salut in Catalonia (Spain). M.M.R. and L.G.-S. are financed by a fellowship 'Juan de la Cierva' from the Spanish Ministry of Science and Innovation (Grant JCI-2011-11488 and JCI-2009-04086, respectively). E.-M.-M. is supported by the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas.

Subjects
Male, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Obesidad, Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], Adipose tissue, Bariatric Surgery, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Índice de masa corporal, Fatty Acids, Nonesterified, Biochemistry, Body Mass Index, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, Endocrinology, Adipocyte, Adipocytes, Medicine, Cytokine TWEAK, biology, Citocinas, Stromal vascular fraction, Middle Aged, Ácidos grasos no esterificados, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Bariatric Surgery [Medical Subject Headings], Anatomy::Cells::Connective Tissue Cells::Adipocytes [Medical Subject Headings], Tumor Necrosis Factors, Cytokines, Female, Adult, medicine.medical_specialty, Check Tags::Male [Medical Subject Headings], Proinflammatory cytokine, Anatomy::Cells::Connective Tissue Cells::Macrophages [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors::Tumor Necrosis Factor-alpha [Medical Subject Headings], Internal medicine, Adipocitos, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Macrófagos, Interleukin 8, Obesity, Interleukin 6, Cirugía bariátrica, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings], Adiponectin, business.industry, Tumor Necrosis Factor-alpha, Macrophages, Biochemistry (medical), Factores de necrosis tumoral, Factor de necrosis tumoral alfa, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Surgery, Check Tags::Female [Medical Subject Headings], chemistry, biology.protein, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Nonesterified [Medical Subject Headings], business
Abstract

Journal Article; Research Support, Non-U.S. Gov't; CONTEXT Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells. OBJECTIVES The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity. DESIGN sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed. RESULTS sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events. CONCLUSION The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα. Yes

Published
2013

4. Tumor necrosis-like weak inducer of apoptosis as a proinflammatory cytokine in human adipocyte cells: up-regulation in severe obesity is mediated by inflammation but not hypoxia

Author

Joan Vendrell, Elsa Maymó-Masip, Matilde R. Chacón, Ana Megia, Francisco J. Tinahones, Antonio Garcia-España, Enric Caubet, Eduardo García-Fuentes, [Vendrell,J, Maymó-Masip,E, Megía,A, Chacón,MR] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Hospital Universitari de Tarragona Joan XXIII, Spain. [Vendrell,J, Chacón,MR, García-España,A] IISPV (Institut d’Investigació Sanitaria 'Pere Virgili'), Universitat Rovira i Virgili, Tarragona, Spain. [Tinahones Madueño,FJ, García-Fuentes,E] Centro de Investigación Biomédica en Red de Fisiopatología, Obesidad y Nutrición, Department of Obesity and Nutrition, Hospital Universitario Virgen de la Victoria, Málaga, Spain. [Caubet,E] Department of Surgery, Hospital St. Pau i Sta Tecla, Tarragona, Spain., and This work was supported by Grants from Fondo de Investigacion Sanitaria PI 08/0733 and CP06/00119 cofinanced by the European Regional Development Fund. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas de Diabetes y Enfermedades Metabólicas Asociadas (CB07/08/ 0012) is an initiative of the Instituto de Salud Carlos III (ISCIII).A.G.-E. is supported by the Research Stabilization Program of the ISCIII-Institut Català de Salut in Catalonia. M.R.C. is supported by a fellowship from the Fondo de Investigación Sanitaria (CP06/00119).

Subjects
Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Biopsy, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], Clinical Biochemistry, Gene Expression, Adipose tissue, Type 2 diabetes, Diabetes Mellitus Tipo 2, Endoplasmic Reticulum, Biochemistry, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Receptors, Tumor Necrosis Factor, Cohort Studies, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, Endocrinology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Techniques, Surgical::Biopsy [Medical Subject Headings], Anoxia, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Endoplasmic Reticulum [Medical Subject Headings], Adipocyte, Adipocytes, Tejido Adiposo, Hypoxia, Endoplasmic Reticulum Chaperone BiP, Cytokine TWEAK, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Cytokine::Receptors, Tumor Necrosis Factor [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Citocinas, General Medicine, TNFSF12 protein, human, TWEAK receptor, Anatomy::Tissues::Connective Tissue::Adipose Tissue [Medical Subject Headings], Obesity, Morbid, Up-Regulation, Cytokine, Adipose Tissue, TWEAK Receptor, Anatomy::Cells::Connective Tissue Cells::Adipocytes [Medical Subject Headings], Tumor Necrosis Factors, Cytokines, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity::Obesity, Morbid [Medical Subject Headings], Tumor necrosis factor alpha, medicine.symptom, Signal Transduction, medicine.medical_specialty, Western Blotting, Línea Celular, Obesidad Mórbida, Expresión Génica, Blotting, Western, Inflammation, Context (language use), Biology, Cell Line, Proinflammatory cytokine, Translational Highlights from Jcem, Internal medicine, Anatomy::Cells::Connective Tissue Cells::Macrophages [Medical Subject Headings], Adipocitos, medicine, Humans, Macrófagos, Molecular Biology, Regulación hacia Arriba, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Respiratory::Anoxia [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings], Inflamación, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings], Factores de Necrosis Tumoral, Macrophages, Biochemistry (medical), Transducción de Señal, Hypoxia (medical), medicine.disease, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Biopsia, Diabetes Mellitus, Type 2, chemistry, Immunology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Electrophoresis::Blotting, Western [Medical Subject Headings], Tumor Necrosis Factor Inhibitors, Retículo Endoplásmico, Receptores del Factor de Necrosis Tumoral, Estudios de Cohortes, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings]
Abstract

Context: Adipose tissue hypoxia and endoplasmic reticulum (ER) stress may link the presence of chronic inflammation and macrophage infiltration in severely obese subjects. We previously reported the up-regulation of TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in adipose tissue of severely obese type 2 diabetic subjects. Objectives: The objective of the study was to examine TWEAK and Fn14 adipose tissue expression in obesity, severe obesity, and type 2 diabetes in relation to hypoxia and ER stress. Design: In the obesity study, 19 lean, 28 overweight, and 15 obese nondiabetic subjects were studied. In the severe obesity study, 23 severely obese and 35 control subjects were studied. In the type 2 diabetes study, 11 type 2 diabetic and 36 control subjects were studied. The expression levels of the following genes were analyzed in paired samples of sc and visceral adipose tissue: Fn14, TWEAK, VISFATIN, HYOU1, FIAF, HIF-1a, VEGF, GLUT-1, GRP78, and XBP-1. The effect of hypoxia, inflammation, and ER stress on the expression of TWEAK and Fn14 was examined in human adipocyte and macrophage cell lines. Results: Up-regulation of TWEAK/Fn14 and hypoxia and ER stress surrogate gene expression was observed in sc and visceral adipose tissue only in our severely obese cohort. Hypoxia modulates TWEAK or Fn14 expression in neither adipocytes nor macrophages. On the contrary, inflammation up-regulated TWEAK in macrophages and Fn14 expression in adipocytes. Moreover, TWEAK had a proinflammatory effect in adipocytes mediated by the nuclear factor-κB and ERK but not JNK signaling pathways. Conclusions: Our data suggest that TWEAK acts as a pro-inflammatory cytokine in the adipose tissue and that inflammation, but not hypoxia, may be behind its up-regulation in severe obesity.

Published
2010

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