IL-10 Controls Cystatin C Synthesis and Blood Concentration in Response to Inflammation through Regulation of IFN Regulatory Factor 8 Expression

Xu, YK; Schnorrer, P; Proietto, A; Kowalski, G; Febbraio, MA; Acha-Orbea, H; Dickins, RA; Villadangos, JA

Author(s): Xu, YK; Schnorrer, P; Proietto, A; Kowalski, G; Febbraio, MA; Acha-Orbea, H; Dickins, RA; Villadangos, JA;
Details: Publication Year 2011-03-15,Volume 186,Issue #6,Page 3666-3673
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
Abstract: Cystatin C (CstC) is a cysteine protease inhibitor of major clinical importance. Low concentration of serum CstC is linked to atherosclerosis. CstC can prevent formation of amyloid beta associated with Alzheimer's disease and can itself form toxic aggregates. CstC regulates NO secretion by macrophages and is a TGF-beta antagonist. Finally, the serum concentration of CstC is an indicator of kidney function. Yet, little is known about the regulation of CstC expression in vivo. In this study, we demonstrate that the transcription factor IFN regulatory factor 8 (IRF-8) is critical for CstC expression in primary dendritic cells. Only those cells with IRF-8 bound to the CstC gene promoter expressed high levels of the inhibitor. Secretion of IL-10 in response to inflammatory stimuli downregulated IRF-8 expression and consequently CstC synthesis in vivo. Furthermore, the serum concentration of CstC decreased in an IL-10-dependent manner in mice treated with the TLR9 agonist CpG. CstC synthesis is therefore more tightly regulated than hitherto recognized. The mechanisms involved in this regulation might be targeted to alter CstC production, with potential therapeutic value. Our results also indicate that caution should be exerted when using the concentration of serum CstC as an indicator of kidney function in conditions in which inflammation may alter CstC production. The Journal of Immunology, 2011, 186: 3666-3673.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: CYSTEINE PROTEINASE-INHIBITORS; CELL SUBSET DEVELOPMENT; CD8(+) DENDRITIC CELLS; IN-VIVO; ANTIGEN PRESENTATION; MOUSE; GENE; PROTEASES; MUTATION; MICE
Publisher's Version: https://doi.org/10.4049/jimmunol.1001934
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-03-15 12:00:00