Background: Programmed death-ligand 1 (PD-L1) plays a critical role to protect β-cells against immune attack. Interferon regulatory factor 1 (IRF1) is a key transcriptional factor to regulate PD-L1 expression, which is induced by various cytokines through JAK/STAT pathway. Human islet amyloid polypeptide (hIAPP) activates resident macrophages to accelerate proinflammatory phenotype of islets. However, it is still unknown if hIAPP regulates the local inflammatory response in β-cells under immune attack. hIAPP knock-in mice induce diabetic phenotype only following high-fat feeding. In addition, most type 2 diabetic patients who have S20G-IAPP mutation show severe diabetic phenotype; however, other people who have it show only modest or no impairment of glucose tolerance. These evidences suggest that cytotoxic effect of hIAPP is not strong enough by itself, but may require another factor, like local immune dysregulation, to induce diabetic phenotype. These backgrounds encouraged us to investigate if and how hIAPP regulates IRF1/PD-L1 pathway in β-cells.

Methods: We evaluated the effect of hIAPP on IRF1/PD-L1 pathway by using recombinant rat(r) and human IAPP in INS1 cells. Doxycycline-inducible rIAPP- and hIAPP-overexpressing INS1 cells were used to confirm the results. Interferon (INF)-γ was used to activate JAK/STAT pathway.

Results: Recombinant hIAPP rather than rIAPP reduced endogenous and INF-γ-induced PD-L1 expression. Similarly, hIAPP-overexpression reduced PD-L1 expression. Recombinant both rat and human IAPP showed limited effect on phosphorylation of STAT1 and STAT3 induced by INF-γ. Protein levels of IRF1 induced by INF-γ were reduced by recombinant hIAPP; however, its mRNA levels were not reduced. Cycloheximide chase study revealed the destabilization of IRF1 protein under hIAPP treatment.

Conclusion: Our results suggest that hIAPP could destabilize IRF1 protein to reduce PD-L1 expression in INS1 cells.


S. Morita: None. T. Ishibashi: None. H. Ariyasu: None. H. Iwakura: None. M. Nishi: None. H. Furuta: None. T. Akamizu: None.

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