title: Proinflammatory effects of malondialdehyde in lymphocytes.
abstract: Diabetes is an inflammatory disease promoted by alterations in immune cell function. Animal study indicates that T cells are important mediators of inflammation in diabetes. Lipid peroxidation by reactive oxygen species leads to the formation of highly reactive malondialdehyde (MDA), and extensive MDA is found in diabetes. However, the biological functions of MDA have not been studied yet. We hypothesized that increased MDA, as in diabetes, can regulate inflammatory cytokines via specific signaling pathways. This could then result in increased lymphocyte activation and skewing a particular inflammatory subset thereby exacerbates diabetes complications. Commercial cytokine antibody and RT(2)-PCR array profiling were performed with Jurkat T cells grown with or without MDA. Ingenuity pathways analysis (IPA) and pharmacological inhibitors were used for networks and signaling pathway identification, respectively. For validation, real-time PCR, RT-PCR, and Western blots were performed. MDA induced significant increases in 47 key proinflammatory molecules such as IL-25, IL-6, IL-8, ICAM-1, and light mRNA in Jurkat T cells and primary peripheral blood lymphocytes (PBLCs). A significant 2-fold increase in serum MDA also correlated the increased IL-25 and IL-8 mRNA in PBLCs of diabetic patients. Pharmacological inhibitor studies showed that MDA induced its effect via p38MAPK and protein kinase C pathways. Furthermore, IPA uncovered 5 groups of inflammatory networks and placed our candidate genes in canonical IL-6 and NF-κB signaling pathways and also suggested 5 toxic lists and 3 major toxic functions, namely cardiotoxicity, hepatotoxicity, and nephrotoxicity. These new results suggest that MDA can promote lymphocyte activation via induction of inflammatory pathways and networks.
authors.affiliation: Department of Biomedical Science, Bharathidasan University, Tamilnadu, India.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Raghavan
authors.forename: Ganesan
authors.initials: G
authors.lastname: Subramaniyam
authors.forename: Narkunaraja
authors.initials: N
authors.lastname: Shanmugam
mesh_terms: D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008315:Malondialdehyde / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome; D014162:Transfection
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D008315:Malondialdehyde