IL-10 controls cystatin C synthesis and blood concentration in response to inflammation through regulation of IFN regulatory factor 8 expression

Yuekang Xu, Petra Schnorrer, Anna I Proietto, Greg M Kowalski, Mark A Febbraio, Hans Acha-Orbea, Ross Alexander Dickins, Jose A Villadangos

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

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 ? associated with Alzheimer s disease and can itself form toxic aggregates. CstC regulates NO secretion by macrophages and is a TGF-? 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.
Original languageEnglish
Pages (from-to)3666 - 3673
Number of pages8
JournalJournal of Immunology
Volume186
DOIs
Publication statusPublished - 2011
Externally publishedYes

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