Abstract
We have shown the induction of histone deacetylase 3 (HDAC3) in antigen-stimulated rat basophilic leukemia cells via NF-κB. We investigated the role of HDAC3 in allergic skin inflammation. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. Triphasic cutaneous reaction involved induction of HDAC3 and was mediated by HDAC3. HDAC3 showed an interaction with FcεRIβ. Trichostatin A (TSA), an inhibitor of HDAC(s), disrupted this interaction. Cytokine array analysis showed that the down-regulation of HDAC3 led to the decreased secretion of monocyte chemoattractant protein 1 (MCP1). FcεRI was necessary for induction of HDAC3 and MCP1. ChIP assays showed that HDAC3, in association with Sp1 and c-Jun, was responsible for induction of MCP1 expression. TSA exerted a negative effect on induction of MCP1. HDAC3 exerted a negative regulation on expression of HDAC2 via interaction with Rac1. The down-regulation of HDAC3 or inactivation of Rac1 induced binding of HDAC2 to MCP1 promoter sequences. TSA exerted a negative effect on HDAC3-mediated TpCR. The BALB/c mouse model of PCA involved induction of HDAC3 and MCP1. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Recombinant MCP1 enhanced β-hexosaminidase activity and histamine release and also showed angiogenic potential. TSA exerted a negative effect on PCA. Our data show HDAC3 as a valuable target for the development of allergic skin inflammation therapeutics.
Highlights
The role of histone deacetylase 3 (HDAC3) in allergic skin inflammation remains unknown
We examined whether HDAC3 activity and monocyte chemoattractant protein 1 (MCP1), a downstream target of HDAC3, were necessary for allergic skin inflammation in relation with angiogenesis
Mast cells isolated from ear tissues of BALB/c mice showed an interaction between HDAC3 and Fc⑀RI and an interaction between HDAC3 and Lyn by DNFB stimulation
Summary
Results: HDAC3 interacts with Fc⑀RI and regulates expression of MCP1 through Sp1 and c-Jun to mediate allergic skin inflammation. Conclusion: HDAC3 mediates allergic skin inflammation in relation with angiogenesis by regulating MCP1. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Hypoxia-inducible factor (HIF), an angiogenic factor, is necessary for various allergic inflammatory diseases, including PCA [7]. Mast cells interact with endothelial cells to contribute to angiogenesis in multiple myelomas [11] These reports suggest that allergic inflammation involves vascular permeability and angiogenesis. Conditional deletion of HDAC1 in T cells enhances Th2 cytokine expression in
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