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The serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-gamma to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.