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tosis 37. However, the β1i subunit in the nuclear enriched fraction has also been detected in its catalytically active form 40 and several studies indicate a possible functional role of the immunoproteasome in transcriptional regulation 41-43. The expression pattern, either nuclear or cytoplasmic proteasome expression, can be influenced by the type and dura- tion of fixation 37. However similar pattern was observed in surgical and post-mortem TSC brain tissue.
One of the major regulatory factors of immunoproteasome induction is inflam- mation 43, 44. Several studies confirmed the occurrence of complex inflammatory changes, involving both glial and neuronal cells, and activation of the IL-1β pathway, particularly in FCD II and TSC 20, 34, 35, 45-48. Thus the pro-inflammatory environment may contribute to the activation of the proteasome system, particularly to the induction and expression of the immunoproteasome subunits. Accordingly, our in vitro studies in human astrocytes and FCD cultures indicate that IL-1β treatment increases the induction of in particular the immunoproteasome subunits β1i and β5i, with increase of their perinuclear-nuclear localization. This observation supports the role of astrocytes as targets of regulation of the immunoproteasome under various conditions associated with activation of the IL-1β pathway 16 and indicates that pro-inflammatory cytokines, other than IFN-γ may regulate immunoproteasome expression. Activation of inflammatory pathways, includ- ing IL-1β, may also play a role in the regulation of immunoproteasome expression in other cell types, such as neurons. Accordingly, we found a positive correlation between the expression of immunoproteasome subunits in both glial and neuronal cells and the expression of IL-1β within the dysplastic area in FCD II and in TSC specimens. Moreover, increasing evidence supports the role of the immunoproteasome in the activation of the NF-κB pathway, modulation of pro-inflammatory cytokine production and oxida- tive stress response 9, 43, 49-52. Induction of the β5i subunit has also been shown in vivo following activation of the Toll-like receptor 4 (TLR4)-mediated NF-κB signaling path- way by LPS 53. Thus, we may speculate about the existence of a reinforcing feedback loop between NF-κB pathway and the immunoproteasome system, which may play a crucial role in perpetuating the pro-epileptogenic inflammatory response in epilepsy. Interestingly, Mishto, et al., 18 provide additional experimental evidence of the regulation of β5i subunit by TLR4 signaling in epileptogenic tissue.
The immunoproteasome is known to improve MHC class I (MHC-I) antigen pre- sentation and has been suggested to have a central function at the interface between the innate and adaptive immune system (reviewed in 11). Interestingly, FCD II and TSC spe- cimens are characterized by prominent activation of both innate and adaptive immune responses (for review see 20, 36). Moreover, recent studies provide evidence of an upreg- ulation of MHC-I, involving also balloons/giant cells and neurons, in both FCD II and TSC specimens 54.
FCD II and TSC cases are characterized by architectural or cellular changes asso- ciated with mTOR pathway activation 20, 21. The innate and adaptive immune responses have also been shown to be influenced by the mTOR pathway 55-57. Moreover, the mTOR complex 1 (mTORC1) has been identified as key regulator of autophagy 58, 59, a pathway which is defective in FCD II and TSC 60. Increasing evidence indicates a strong relation- ship with tight coordination between the autophagy and the proteasome systems 61. Thus, we cannot exclude a role of mTOR in the regulation of the proteasome system,





























































































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