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Multiple sclerosis is believed to be triggered by the interplay between the environmental and genetic factors. In contrast to the Paleolithic diet, the modern Western diet is high in Na

Dexamethasone augments mitochondrial protein abundance. The translocase of the outer membrane (Tom) of mitochondria plays a major role in importing largely cytosolically synthesized proteins into mitochondria. We hypothesize that dexamethasone upregulates the Tom transport system, leading to increase of mitochondrial protein localization. Tom20 and Tom70 are the two major subunits. Dexamethasone increased Tom20 and Tom70 mRNA levels by 53 ± 11% and 25 ± 9% and mitochondrial protein abundance by 27 ± 7% and 25 ± 4% (p

Multiple sclerosis disproportionally affects women. The present study was undertaken to determine whether NFAT5 contributed to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and if it did, whether the impact was sex associated. NFAT5 haplodeficiency reduced the disease severity only in female mice. This effect was associated with significant increases in frequency of T regulatory (Treg) cells in the CNS (from 1.45 ± 0.39% to 3.73 ± 0.94%) and spleen from (0.31 ± 0.06% to 0.94 ± 0.29%) without significantly affecting the CNS CD4

Our previous demonstration that severe experimental autoimmune encephalomyelitis (EAE) increases MnSOD protein abundance in the mouse kidney cortex led this study to elucidate the underlying mechanism with monensin-treated HEK293 cells as a model. Severe EAE increases mitochondrial protein abundance of SGK1 kinase and Tom20, a critical subunit of mitochondrial translocase in the renal cortex. In HEK293 cells, catalase inhibits monensin-induced increases of mitochondrial SGK1 and Tom20 protein levels. Further, GSK650394, a specific inhibitor of SGK1 reduces monensin-induced increase of mitochondrial protein abundance of Tom20 and MnSOD. Finally, RNAi of Tom20 reduces the effect of monensin on MnSOD. MnSOD and Tom20 physically associate with each other. In conclusion, in HEK293 cells, mitochondrial reactive oxygen species increase protein abundance of mitochondrial SGK1, which leads to a rise of mitochondrial Tom20, resulting in importing MnSOD protein into the mitochondria. This could be a mechanism by which severe EAE up-regulates mitochondrial MnSOD in the kidney cortex.

Th1 and Th17 cells contribute to the pathogenesis of multiple sclerosis (MS) and EAE, an animal model of MS. Th1 cells are characterized by the abundant expression of IFN-γ, whereas Th17 cells express high levels of IL-17. T cell activation leads to the nuclear translocation of nuclear factors and activators of T-cells (NFATs), which contribute to the expression of IFN-γ and IL-17. NFAT5 is the newest member of the NFAT family, however, its role in the pathogenesis of EAE is unknown. We are therefore studying MOG35–55-induced EAE in mice with a global heterozygous knockdown of NFAT5 (NFAT5+/−, NFAT5−/−is lethal) with NFAT5+/+ mice as a control. Interestingly, we found that the knockdown of NFAT5 actually increased EAE induction rate from 65% to 74% and delayed the recovery of EAE, indicating that NFAT5 is protective against the disease. Naïve CD4 cell differentiation reveals that the NFAT5 knockdown increased IFN-γ expression without significantly affecting IL-10 expression in Th1 cells. In vitro differentiation of Th17 cells from NFAT5+/− mice was not successful. IL-6 and protein tyrosine phosphatase SHP-1 have been demonstrated to inhibit IFN-γ expression in Th1 cells. To study the mechanisms by which NFAT5 knockdown increases IFN-γ expression in Th1 cells, we have examined the effects of NFAT5 knockdown on IL-6 and SHP-1. NFAT5 knockdown had no significant effect on IL-6 mRNA level. Instead, our ongoing experiments show that knockdown of NFAT5 reduces SHP-1 mRNA level by 38% (n=3, p=0.11) with a concomitant 44% increase in phosphorylation of Y705 of STAT3, one of its targets (n=3, p=0.2), and has no significant effect on SHP-2 mRNA level. In conclusion: NFAT5 inhibits EAE possibly by suppressing the expression of IFN-γ in Th1 cells.