Galectin-9 Protein Expression in Endothelial Cells Is Positively Regulated by Histone Deacetylase 3

Abstract

Galectin-9 expression in endothelial cells can be induced in response to inflammation. However, the mechanism of its expression remains unclear. In this study, we found that interferon-␥ (IFN-␥) induced galectin-9 expression in human endothelial cells in a time-dependent manner, which coincided with the activation of histone deacetylase (HDAC). When endothelial cells were treated with the HDAC3 inhibitor, apicidin, or shRNA-HDAC3 knockdown, IFN-␥-induced galectin-9 expression was abolished. Overexpression of HDAC3 induced the interaction between phosphoinositol 3-kinase (PI3K) and IFN response factor 3 (IRF3), leading to IRF3 phosphorylation, nuclear translocation, and galectin-9 expression. HDAC3 functioned as a scaffold protein for PI3K/IRF3 interaction. In addition to galectin-9 expression, IFN-␥ also induced galectin-9 location onto plasma membrane, which was HDAC3-independent. Importantly, HDAC3 was essential for the constitutive transcription of PI3K and IRF3, which might be responsible for the basal level of galectin-9 expression. The phosphorylation of IRF3 was essential for galectin-9 expression. This study provides new evidence that HDAC3 regulates galectin-9 expression in endothelial cells via interaction with PI3K-IRF3 signal pathway.Galectins are a family of lectins classified into three groups (prototype, tandem-repeat, and chimera-type galectins) according to their conserved carbohydrate recognition domains and their ability to bind to ␤-galactosides (1). To date, 15 galectin proteins have been identified in mammals displaying wide tissue distribution whereas some have higher tissue specificity. They can function intracellularly and extracellularly. Accumulating evidence implicates galectins as immunoregulatory mediators in diverse physiological and pathological processes such as immune and inflammatory responses, tumor immunity, wound repair, and atherosclerosis (2, 3).Galectin-9 belongs to the tandem-repeat galectins that contain two carbohydrate recognition domains, mainly functioning as a chemoattractant of eosinophils (4, 5) and immunomodulation in a physiological and pathological setting (6, 7). Galectin-9 exerts its immunosuppressive roles through its receptor, T cell immunoglobin domain and mucin domain 3 (Tim3), 2 which can increase the survival of transplants (6, 8 -11). Galectin-9 may also induce proinflammatory cytokines in monocytes and T cells in a Tim3-independent manner (12, 13). Galectin-9-deficient mice show enhanced susceptibility to arthritic induction with increased CD4 ϩ TIM3 ϩ cells (14) and were prone to increased mortality and died within 72 h of LPS induction (15). In endothelial cells, galectin-9 can be induced by interferon-␥ (IFN-␥) (16, 17) and double-stranded RNA (18), which may play a role in inflammatory response by regulating interactions between the vascular wall and eosinophils. However, the mechanism of how galectin-9 is expressed in endothelial cells is unknown.Histone deacetylase 3 (HDAC3) belongs to class I HDAC family (19). Distinct from other family membe...

Galectin-9 Is a Suppressor of T and B Cells and Predicts the Immune Modulatory Potential of Mesenchymal Stromal Cell Preparations

“…In the endothelium, Gal-9 acts as a chemoattractant for eosinophils and increased adhesion [25]. This process is supported by HDAC3, which induced the interaction of phosphoinositol 3-kinase (PI3K) and IFN response factor 3(IRF3), resulting in phosphorylation of IRF3, its nuclear translocation, and increased Gal-9 expression [37]. Whether this signaling cascade is responsible for enhanced Gal-9 expression in MSCs as well, still has to be elucidated.…”

Histone Deacetylase 3 Unconventional Splicing Mediates Endothelial-to-mesenchymal Transition through Transforming Growth Factor β2

“…Structural analyses of HDAC3 protein indicate that the C-terminal domain is the deacetylase catalytic domain and is responsible for gene transcriptional repression, whereas the N-terminal domain is responsible for oligomerization of HDAC3 itself and interaction with other HDACs and proteins, such as Akt1 (25,47). In addition to its deacetylase activity, HDAC3 may function as a scaffold in complexes, in which the N-terminal domain plays an essential role (48,49). The HD3␣ isoform retains the N-terminal domain.…”

Intestinal Epithelium-Derived Galectin-9 Is Involved in the Immunomodulating Effects of Nondigestible Oligosaccharides

“…Regulation of galectin expression is largely unknown, but the data presented in the current study indicate that IEC only secrete galectin-9 upon apical exposure to CpG DNA and scGOS/lcFOS under inflammatory conditions. In endothelial cells, galectin-9 expression is regulated by the proinflammatory cytokine IFN-γ in a PI3K/IRF3-signaling pathway, involving HDAC3 [32,33]. …”