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TNF, IL 1B, lymphotoxin. and TGF B are identified Epoxomicin to bring about cell death in oligodendrocytes. TNF and IL 1B were not detected in the culture supernatants of oligodendrocytes that were incubated with live B. burgdorferi for 48 h. TGF B and LT were not among the mediators that were detected by the human 14 plex array that we utilized and may well properly have been present in the culture supernatants. TNF, LT, and TGF B were shown to induce apoptosis in oligodendrocytes when added exogenously, while IL 1B brought on glutamate mediated exci totoxic death of oligodendrocytes co cultured with astro cytes and microglia. or when injected intra Epoxomicin cerebrally in neonatal rats. The prospective of CCL2, IL 6, and or IL eight to induce oligodendrocyte apoptosis has not been documented thus far in the literature.
Actually, IL 6 is identified to promote the survival of oligodendrocytes in culture. IL eight has been shown to induce the expression of pro inflammatory pro teases, matrix metalloproteinases MMP 2 and MMP 9, cell cycle protein cyclin D1, an early marker Epoxomicin for G1 S transition and pro apoptotic protein Bim. and cell death in cultured neu rons in 24 h. CCL2 is implicated in mediating oligodendrocyte white matter damage indirectly by medi ating the influx of immune cells including T cells and macrophages, resulting in cytotoxic damage of your myelin sheath of axons, followed by phagocytosis of myelin deb ris, culminating in demyelination and axonal damage. A doable involvement of cytotoxic cells in the immune response against B. burgdorferi has been suggested determined by in vitro studies.
as well as reports indicating the presence of a cytolytic phenotype of IFN generating cells from individuals with LNB. It is actually most likely that a simi lar mechanism may be mediating the demyelination and axonal degeneration resulting in white matter lesions seen in LNB. The anti inflammatory Protein precursor effect of dexamethasone, a glucocorticoid utilized in the treatment of immune mediated inflammatory diseases is properly documented. Dexamethasone has been shown to correctly re duce the levels of IL 6, IL 1B, and TNF released from human monocytes stimulated with endotoxin to beneath background levels. Dexamethasone lowered the levels of CCL2 in brain and retinal vascular endothelial cells that were activated with pro inflammatory cyto kines IL 1B, TNF, and IFN. The anti inflammatory prospective of dexamethasone to decrease CCL2 and IL eight also has been reported in cultured rheumatoid synovio cytes.
Here PP1 we show that dexamethasone can re duce the levels of CCL2, Epoxomicin IL 6, and IL eight as induced by B. burgdorferi in differentiated human oligodendrocytes. Clinical improvement was seen in a serious case of neu roborreliosis showing encephalomyelitis with polyneur opathy, when treated together with the classically recommended 2 to 4 weeks of anti microbial agents in mixture with steroids. Dexamethasone has been shown to suppress CCL2 pro duction by means of mitogen activated protein kinase phosphatase 1 dependent inhibition of Jun N terminal kinase and p38 MAPK in activated rat microglia. MAPK cas cades are signal transduction pathways that play crucial regulatory roles in the biosynthesis of pro inflammatory cytokines including IL 6, IL eight, and CCL2.
MAKP P1, a member of your Map Kinase Phosphatase loved ones, is essential for the dephosphorylation deactivation of MAPK p38 and JNK, thereby limiting pro inflammatory cytokine PP1 biosyn thesis in innate immune cells exposed to microbial compo nents or infectious agents. MAPK including p38 and JNK may be involved in the signaling mechanisms beneath lying both inflammation and apoptosis. Earlier we had documented the function of p38 MAPK, Erk1, and Erk 2 in mediating the production of IL 6 and TNF, also as apop tosis, in rhesus astrocytes as induced by lipoproteins of B. burgdorferi. MAPK signaling pathways may well certainly be involved in regulating both inflammation and apoptosis as induced by B. burgdorferi in human oligodendrocytes, also as in the modulatory effect of dexamethasone that we observed.
Conclusions In this study we've got established that live B. burgdorferi are capable of eliciting inflammatory mediators, particu larly IL 6, IL eight, and CCL2, as well as inducing apop tosis in human oligodendrocyte cultures in vitro, by activating caspase Epoxomicin 3. Oligodendrocytes would be the myelinating cells of your CNS that myelinate neuronal axons, providing saltatory conduction of action potentials and right func tion of your CNS. The function of oligodendrocyte death in MS is properly established. Many of the earliest patho logical adjustments in inflammatory lesions seen in MS are increases in oligodendrocyte apoptosis. Depending on the observations of this study we propose that neurologic injury in the CNS for the duration of an infection together with the Lyme dis ease spirochete B. burgdorferi could be mediated in aspect by the direct action of your spirochetes on oligodendrocytes or by means of inflammation mediated by B. burgdorferi in oligoden drocytes. PP1 As oligodendrocytes are essential for the survival and optimum function of neurons. oligodendrocyte dam a