Targeted Delivery of the HLA-B∗27-Binding Peptide into the Endoplasmic Reticulum Suppresses the IL-23/IL-17 Axis of Immune Cells in Spondylarthritis.
Hui-Chun YuKuang-Yung HuangMing-Chi LuHsien-Lu HuangSu-Qin LiuNing-Sheng LaiHsien-Bin HuangPublished in: Mediators of inflammation (2017)
Ankylosing spondylitis (AS) is highly associated with the expression of human leukocyte antigen-B27 (HLA-B∗27). HLA-B∗27 heavy chain (B27-HC) has an intrinsic propensity to fold slowly, leading to the accumulation of the misfolded B27-HC in the endoplasmic reticulum (ER) and formation of the HLA-B∗27 HC homodimer, (B27-HC)2, by a disulfide linkage at Cys-67. (B27-HC)2 displayed on the cell surface can act as a ligand of the killer-cell Ig-like receptor (KIR3DL2). (B27-HC)2 binds to KIR3DL2 of NK and Th17 cells and activates both cells, resulting in the activation of the IL-23/IL-17 axis to launch the inflammatory reaction in AS patients. However, activation of the IL-23/IL-17 axis originally derived from the HLA-B∗27 misfolding in the ER needs to be characterized. In this study, we delivered two HLA-B∗27-binding peptides, KRGILTLKY and SRYWAIRTR, into the ER by using a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) vehicle. Both peptides are derived from the human actin and nucleoprotein of influenza virus, respectively. Our results demonstrated that targeted delivery of both HLA-B∗27-binding peptides into the ER can promote the HLA-B∗27 folding, decrease the levels of (B27-HC)2, and suppress the activation of the IL-23/IL-17 axis in response to lipopolysaccharide. Our findings can provide a new therapeutic strategy in AS.
Keyphrases
- endoplasmic reticulum
- ankylosing spondylitis
- induced apoptosis
- endothelial cells
- end stage renal disease
- estrogen receptor
- signaling pathway
- chronic kidney disease
- stem cells
- gene expression
- toll like receptor
- cell cycle arrest
- breast cancer cells
- cell surface
- poor prognosis
- cell proliferation
- ejection fraction
- long non coding rna
- inflammatory response
- newly diagnosed
- cell death
- immune response
- prognostic factors
- transcription factor
- dna binding
- endoplasmic reticulum stress
- pi k akt