title: IL-10 controls cystatin C synthesis and blood concentration in response to inflammation through regulation of IFN regulatory factor 8 expression.
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 β associated with Alzheimer's disease and can itself form toxic aggregates. CstC regulates NO secretion by macrophages and is a TGF-β 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.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. ykxu@wehi.edu.au
authors.forename: Yuekang
authors.initials: Y
authors.lastname: Xu
authors.forename: Petra
authors.initials: P
authors.lastname: Schnorrer
authors.forename: Anna
authors.initials: A
authors.lastname: Proietto
authors.forename: Greg
authors.initials: G
authors.lastname: Kowalski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.forename: Jose A
authors.initials: JA
authors.lastname: Villadangos
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D055316:Cystatin C / Q000096:biosynthesis* / Q000097:blood* / Q000172:deficiency; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000099185:Interferon Regulatory Factor-8
chemical_list: D055316:Cystatin C; D018836:Inflammation Mediators; D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D000099185:Interferon Regulatory Factor-8; C525031:Cst3 protein, mouse; C556062:IL10 protein, mouse