Abstract
Abstract Proteinase inhibitor 9 (PI-9) - the only known natural antagonist of the lymphocyte protease granzyme B (GrB) - is an intracellular serpin expressed in lymphocytes and monocyte-derived cells. By intracellular flow cytometry, we have previously shown that ex-vivo stimulation by lipopolysaccharides leads to upregulation of PI-9 within 24 hours in the monocyte, but not the lymphocyte fraction; this can be inhibited by the NF-kappaB inhibitor pyrrolidin dithiocarbamate (PTDC). Glycogen synthase kinase 3 (GSK) is a lithium-inhibitable, constutitively active serine/threonine kinase that controls a number of intracellular functions, especially those involving NF-kappaB regulated genes. We now asked whether lithium-induced inhibition of GSK might influence expression of PI-9 in monocytes and lymphocytes. A 24 hours incubation assay was done using heparinized full blood of healthy volonteers, and PI-9 expression was analysed by intracellular flow cytometry. We found that lithium chloride leads to PI-9 upregulation in monocytes at a medium concentration (1.5 μM), which could not further be enhanced by higher concentrations (10 or 20 μM lithium chloride). In lymphocytes, no alteration of PI-9 expression was induced. When cells were stimulated by LPS in the presence of lithium, only marginal additional upregulation of PI-9 could be induced. Our data show that a lithium-regulated factor, probably GSK, is involved in PI-9 expression in monocytes, down-regulating PI-9 in resting cells. Since it has been shown that PI-9 over-expression in antigen presenting cells, e.g. dendritic cells, leads to an enhanced immune response, our finding may be relevant for specific immune regulation. Pharmacological manipulation of PI-9 expression may represent a useful tool to study immune regulatory mechanisms as well as for therapy .
Published Version
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