Mechanisms of immunoregulation by serine proteinase inhibitor and its application of therapy for rheumatic disease

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1) NK cell death and serpin proteinase inhibitor 9 (PI-9)Here we show that NK cell activation is accompanied by the leakage of granzyme B from intracellular granules into the cytoplasm. Evidence for granzyme B leakage includes the formation of granzyme B/ serine proteinase inhibitor 9 (PI-9) complexes that are detected by immunoprecipitation as well as colocalization of granzyme B and PI-9 detected by immunocytochemistry. The proapoptotic molecule Bid, a specific substrate for granzyme B, was cleaved within 2 min following CD2-induced NK cell activation, suggesting that granzyme B triggers apoptosis by directing Bid to mitochondrial membranes. The granzyme B/PI-9 protein ratio was found to mirror the percentage of CD2-induced NK cell death, suggesting that an excess of leaked granzyme B over its inhibitor is a major determinant of cell death. We suggest that granzyme B leakage-induced cell death (GLCD) is an important determinant of activation-induced NK cell death and that this process may be important for the fate of NK cells which encounter malignant cells or virus-infected cells.2) Rheumatoid arthritis (RA) and PI-9We examined the titer of IL-1β and IL-18 in sera and synovium derived from same RA patients by ELISA. Both IL-1β and IL-18 were produced from RA synovium. In immunohistochemistry, PI-9 was stained in macrophage-like synovial cells (type A). Both caspase 1 and PI-9 were detected in RA synovium using western blotting study. The caspase 1/PI-9 protein ratio was found to mirror the production of IL-1β, but not IL-18 from synovium, suggesting that PI-9 may regulate IL-1β production via caspase 1 inhibition.PI-9 plays the critical roles for the regulation of NK cell death and IL-1β production from RA synovium.