Abstract
Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1–4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1–4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.
Highlights
Major histocompatibility complex (MHC) molecules, known as histocompatibility antigens or human leucocytes antigens (HLA) in humans, are highly polymorphic glycoproteins encoded by MHC class I and MHC class II genes
In an attempt to identify novel immune-regulatory natural products (NPs), we recently reported on the ability of guttiferone J (1), a polyprenylated polycyclic acylphloroglucinol (PPAP) isolated from a Garcinia virgata herbal extract [16], to reduce inflammation as well as immunogenicity of the endothelium by inhibiting cytokine signaling pathways [17]
To decipher the mechanisms involved in the inhibition of MHC molecules mediated by PPAPs, we employed quantitative real time reverse transcription (RT)-PCR to quantify cellular mRNA levels and we focused on the IFNγ signaling that mediate the regulation of most MHC molecules
Summary
Major histocompatibility complex (MHC) molecules, known as histocompatibility antigens or human leucocytes antigens (HLA) in humans, are highly polymorphic glycoproteins encoded by MHC class I and MHC class II genes. Classical MHC molecules are triggers of innate and adaptive immune responses against pathogens and tumors [1]. They are involved in the presentation of peptide antigens to T cells. MHC class II molecules provide antigen presentation to induce antigen-specific CD4 T cells while MHC class I molecules trigger the activation of CD8 T cells to generate cytotoxic T lymphocytes and natural killer (NK) cells to eradicate infected or transformed cells [2]. As a part of the immune response, to enhance lymphocyte activation, expression of MHC molecules is upregulated by interferon-γ (IFNγ), which transduces signal via the Janus tyrosine kinase (Jak) and the latent cytosolic factor, signal transducer and activator of transcription (STAT). MHC class II transactivator (CIITA) is a global regulator involved in basal and IFNγ mediated MHC transcription in two distinct ways: as a transcriptional activator that nucleate an enhanceosome and as a transcription factor with acetyltransferase and kinase activities [3,4]
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