transforming-growth-factor-beta and Neuritis

We investigated the in vitro anti-inflammatory activity of 1(10),4-furanodien-6-one, one the most active compounds of the hexane extract of Commiphora erythraea (Ehrenb.) Engl., by exposing microglial BV-2 cells to lipopolysaccharide. We showed that furanodien-6-one pre-treatment restored cell viability and ROS to control levels while halving NO generation. Production of pro-inflammatory IL-6, IL-23, IL-17, TGF-β, and INF-γ, significantly induced by LPS, was also markedly reduced by furanodien-6-one treatment. We further showed that furanodien-6-one protects primary neuronal cultures against the inflammatory/toxic insults of LPS-treated BV-2 conditioned media, indicating that furanodien-6-one exerts anti-inflammatory/cytoprotective effects in neuronal cells. We then investigated whether furanodien-6-one exerts anti-inflammatory properties in an in vivo model of microglial activation. In adult mice ip-injected with LPS we found that furanodien-6-one had strong cerebral anti-inflammatory properties by inhibiting liver and brain TNFα as well as IL-1β expression. Results were not unexpected since FTIR-metabolomic analyses showed that furanodien-6-one-treated mice had a reduced dissimilarity to control animals and that the response to LPS treatment was markedly modified by furanodien-6-one. In conclusion our data provide strong evidence of the anti-inflammatory properties of furanodien-6-one that could be exploited to counteract degenerative pathologies based on neuroinflammation.

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Cells, Cultured; Cerebrum; Commiphora; Furans; Heterocyclic Compounds, 2-Ring; Interferon-gamma; Interleukin-1beta; Interleukins; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Microglia; Neuritis; Neurons; NF-kappa B; Nitric Oxide; Plant Extracts; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by (137)Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with (137)Cs at a dose of 400Bqkg(-1), which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-alpha and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-alpha, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of (137)Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to (137)Cs.

Topics: Animals; Cesium Radioisotopes; Chernobyl Nuclear Accident; Cytokines; Enzyme Induction; Enzyme-Linked Immunosorbent Assay; Frontal Lobe; Gene Expression; Hippocampus; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Neuritis; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Clusterin; Humans; Immunologic Factors; Immunosuppression Therapy; Myelin Sheath; Nerve Regeneration; Neuritis; Peripheral Nervous System Diseases; Schwann Cells; Transforming Growth Factor beta

Growing evidence indicates that amyloid (A beta) deposition and phagocyte activation participate in inflammatory reactions in the brain during the course of Alzheimer's disease. To further investigate the effects of A beta-phagocyte interaction, we examined the production of proinflammatory (IL-1beta, IL-6), chemotactic (MIP-1alpha, IP-10) and inhibitory (IL-1Ra, IL-10 and TGFbeta1) cytokines by cultured human monocytes and mouse microglial cells upon stimulation with A beta[25-35]. Northern blot analysis and specific immunoassays demonstrated that A beta[25-35] triggers mRNA expression and release of IL-1beta, IL-1Ra and MIP-1alpha but not of IL-6, IL-10, TGFbeta1 and IP-10 from human monocytes. Similar results were obtained by examining the production of IL-1beta, IL-6 and IL-10 from mouse microglial cells in the same experimental conditions. Taken together, these data indicate that A beta-phagocyte interaction can drive a different response towards cytokine production by monocytes and microglia, with a particular proinflammatory trend, and further support a role for A beta deposition as a triggering factor of inflammatory events in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents; Antirheumatic Agents; Cell Line; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL10; Chemokines, CXC; Gene Expression Regulation; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-10; Interleukin-6; Macrophage Inflammatory Proteins; Mice; Microglia; Monocytes; Neuritis; Peptide Fragments; Plaque, Amyloid; RNA, Messenger; Sialoglycoproteins; Transforming Growth Factor beta

Experimental autoimmune neuritis (EAN) is a monophasic inflammatory disorder of the peripheral nervous system that resolves spontaneously by molecular mechanisms as yet unknown. We have investigated whether the immunosuppressive cytokine transforming growth factor-beta 1 (TGF-beta 1) might be endogenously expressed in the peripheral nervous system of Lewis rats with actively induced and adoptive transfer EAN. TGF-beta 1 mRNA was upregulated to high levels in sensory and motor roots, spinal ganglia, and sciatic nerve as revealed by quantitative Northern blot analysis and in situ hybridization histochemistry, with peak levels just preceding the first signs of clinical recovery. TGF-beta 1 mRNA was localized to scattered round cells and dense cellular infiltrates, but only rarely to Schwann cell profiles. Double labeling studies revealed macrophages and subpopulations of T cells as the major cellular source of TGF-beta 1 mRNA. TGF-beta 1 protein was visualized immunocytochemically and localized to infiltrating mononuclear cells with peak expression around the same time as mRNA, in addition to some constitutive expression in axons and Schwann cells. Our studies suggest that the spontaneous recovery observed in Lewis rat EAN might be mediated by the endogenous elaboration of TGF-beta 1 within the peripheral nerve, and that macrophages might control their own cytotoxicity by expressing TGF-beta 1.

Topics: Animals; Autoimmune Diseases; Blotting, Northern; Female; Ganglia, Spinal; Immunohistochemistry; In Situ Hybridization; Neuritis; Peripheral Nervous System; Rats; Rats, Inbred Lew; RNA, Messenger; Sciatic Nerve; Spinal Nerve Roots; Time Factors; Transforming Growth Factor beta