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Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum bio-marker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic over-expression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4 T cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced MHC-II presentation due to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells towards pro-inflammatory Th1/Th17 differentiation. This was mediated by augment Erk1/2 MAP kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.
This article was published in the following journal.
Name: Immunology and cell biology
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A member of the S100 PROTEIN FAMILY that regulates INFLAMMATION and the immune response. It recruits LEUKOCYTES, promotes cytokine and chemokine production, and regulates leukocyte adhesion and migration. S100A12 can also function via binding to ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTORS, to stimulate innate immune cells.
An extracellular cystatin subtype that is abundantly expressed in bodily fluids. It may play a role in the inhibition of interstitial CYSTEINE PROTEASES.
A cystatin subtype that has a diverse tissue distribution, target specificity, and functions as an endogenous inhibitor of lysosomal cysteine proteases.
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A pituitary adenylate cyclase-activating peptide receptor subtype found in LYMPHOCYTES. It binds both PACAP and VASOACTIVE INTESTINAL PEPTIDE and regulates immune responses.
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