Abstract
BackgroundKallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Methodology/Principal FindingsUsing murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.Conclusion/SignificanceKLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis.
Highlights
Kallikrein 6 (KLK6) is a secreted serine protease and member of the largest contiguous cluster of serine proteases in the human genome
Cell Death Paradigms To determine the scope of action of KLK6 in altering immune cell survival we examined its effects in a range of cell death paradigms, including those mediated by transmembrane death receptors, such as the Fas receptor, and those which result from cellular stress and activation of intracellular mitochondrial signaling cascades[31]
Since camptothecin-induced lymphocyte apoptosis is enhanced in the presence of mitogens [39], we examined the effects of KLK6 on cell death induced by either camptothecin or ConA alone, or in combination
Summary
Kallikrein 6 (KLK6) is a secreted serine protease and member of the largest contiguous cluster of serine proteases in the human genome. In prior studies we have demonstrated elevated levels of KLK6 occur in active MS lesions and in the serum of patients experiencing a secondary progressive disease course. KLK6 levels have been shown to be present in infiltrating immune cells at sites of CNS inflammation in animal models of MS and to be up regulated in T cells with activation [1,2,3,4]. KLK6 was shown to activate PAR2 in HEK cells to trigger Ca2+ signaling and on aortic endothelial cells to mediate relaxation [9]. Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. We examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur
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