Effect of advanced glycation end products on STING pathway in macrophage

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  • マクロファージにおけるSTING経路に対する終末糖化産物の影響

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<p>2&apos;3&apos;-Cyclic GMP-AMP (cGAMP) is derived from cancer cell and activates innate immune response via stimulator of interferon genes (STING) pathway. STING is an endoplasmic reticulum-localized transmembrane protein and associated with regulation of several signaling pathway. STING bound with cGAMP lead to the phosphorylation of TANK-binding kinase 1 (TBK1). Phosphorylated TBK1 activates interferon regulatory factor 3 (IRF3) and NF-κB, resulting in induction of type 1 interferon and pro-inflammatory cytokines. Type 1 interferon such as IFNβ and CXCL10 has antitumor activity through activation of several immune cells. Therefore, STING pathway play a crucial role in cancer immunity. Advanced glycation end products (AGEs), especially toxic AGEs derived from glycolaldehyde (AGE-3), are biologically reactive compounds associated with diabetic complications and aging-related disorders. Although accumulation of AGEs has been observed in regions of several cancer types, its role for cancer immunity remains unclear. In the present study, we examined the effect of toxic AGEs on the STING pathways in macrophages. In THP-1 cells which is a human monocytic leukemia cell line, cGAMP induced the phosphorylation of TBK1, IRF3 and NF-κB. Glycolaldehyde-derived AGE (AGE3) dose-dependently suppressed cGAMP-induced the phosphorylation of TBK1, IRF3 and NF-κB. These results may suggest that toxic AGE negatively regulate STING pathways of macrophage and suppress cancer immunity.</p>

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