Transcriptional regulation of mouse mast cell protease-2 by interleukin-15.
Mast cells (MCs) play a critical role in innate and adaptive immunity through the release of cytokines, chemokines, lipid mediators, biogenic amines, and proteases. We recently showed that the activities of MC proteases are transcriptionally regulated by intracellularly retained interleukin-15 (IL-15), and we provided evidence that this cytokine acts as a specific regulator of mouse mast cell protease-2 (mMCP-2). Here, we show that in wild-type bone marrow-derived mast cells (BMMCs) IL-15 inhibits mMCP-2 transcription indirectly by inducing differential expression and mMCP-2 promoter binding of the bifunctional transcription factors C/EBPbeta and YY1. In wild-type BMMCs, C/EBPbeta expression predominates over YY1 expression, and thus C/EBPbeta preferentially binds to the mMCP-2 promoter. In IL-15-deficient BMMCs, the opposite is found: YY1 expression predominates and binds to the mMCP-2 promoter at the expense of C/EBPbeta. Hypertranscription of the mMCP-2 gene in IL-15-deficient BMMCs is associated with histone acetylation and, intriguingly, with methylation of non-CpG dinucleotides within the MCP-2 promoter. This suggests a novel model of cytokine-controlled protease transcription: non-CpG methylation maintains a chromosomal domain in an "open" configuration that is permissive for gene expression.
Division of Immunobiology, Department of Immunology and Cell Biology, Research Center Borstel, 23845 Borstel, Germany.
Farhad
F
Mirghomizadeh
Jörn
J
Bullwinkel
Zane
Z
Orinska
Ottmar
O
Janssen
Arnd
A
Petersen
Prim B
PB
Singh
Silvia
S
Bulfone-Paus
D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D053818:Chymases / Q000096:biosynthesis*; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry; D006801:Humans; D019409:Interleukin-15 / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; D006657:Histones; D019409:Interleukin-15; C083294:chymase 2; D053818:Chymases