Effect of lipid oxidation associated or not with advanced glycation end-products on intracellular signaling pathways and on the expression of inflammatory mediators

• Grant number: 10/06589-8
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2010
• End date: July 31, 2012
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Carlos Rossa Junior
• Grantee: Carlos Rossa Junior
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Silvana Regina Perez Orrico

Abstract

Diabetes is a relevant public health problem due to the high morbidity and mortality rates associated with its complications. These diabetes-associated complications are directly related to the modulation of the immune response by the accumulating advanced glycation end-products (AGEs). The AGEs interact with their multi-ligand receptor, RAGE, expressed in diverse cell types. Diabetic patients also present increased susceptibility to infections, demonstrating the influence of diabetes on the immune response. Periodontal diseases are one type of chronic infection found in diabetic patients with increased prevalence and severity. In fact, periodontal diseases are considered one of the 'classic' diabetes-associated complications. Atherosclerosis is another 'classic' complication of diabetes, which is considered the main cause of mortality among diabetics. Atherosclerosis is a chronic process profoundly influenced by increased serum levels of lipoproteins, especially of oxidized low-density lipoproteins (oxLDL). There is abundant information on the effects of oxLDL and AGEs on the immune response; however frequently the reports are contradictory due to variations on the experimental models (including cell type, treatment periods, and source, method of preparation and concentration of oxLDL and AGEs). The approach of studying 'candidate genes' also contributes to the conflicting information because it yields a partial evaluation of a highly complex cytokine network. There is paucity of information regarding the possible synergistic effects of oxLDL and AGEs on the modulation of the immune response to microbial stimuli (e.g., in the more frequent infections observed in diabetics, such as periodontal diseases). Preliminary data obtained in a clinical study by our group demonstrate an association of an increased severity of periodontal disease in diabetic patients with high levels of oxLDL. The hypothesis we intend to test in this proposal is that oxLDL and AGEs have synergistic effects on the modulation of the immune response to microbial stimuli. The specific aims we propose to test this hypothesis are: 1) To determine the effects of oxLDL and of the axis AGE-RAGE on proliferation and apoptosis of monocytes and T cells; 2) To describe the effects of oxLDL and AGE on the profile of inflammatory mediators expressed by monocytes and T cells stimulated by bacterial LPS; 3) To evaluate role of oxLDL and AGEs on LPS-induced activation of signaling pathways relevant for the expression of inflammatory mediators. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FRASNELLI, S. C. T.; DE MEDEIROS, M. C.; BASTOS, A. DE S.; COSTA, D. L.; ORRICO, S. R. P.; ROSSA JUNIOR, C.. Modulation of Immune Response by RAGE and TLR4 Signalling in PBMCs of Diabetic and Non-Diabetic Patients. Scandinavian Journal of Immunology, v. 81, n. 1, p. 66-71, JAN 2015. (10/06589-8)

DE MEDEIROS, MARCELL COSTA; TFAILE FRASNELLI, SABRINA CRUZ; BASTOS, ALLINY DE SOUZA; PEREZ ORRICO, SILVANA REGINA; ROSSA JUNIOR, CARLOS. Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB. Journal of Applied Oral Science, v. 22, n. 3, p. 185-193, MAY-JUN 2014. (10/06589-8)