Effect of Corticosteroids on Peptide Transporter 2 Function and Induction of Innate Immune Response by Bacterial Peptides in Alveolar Epithelial Cells

In the lung alveolar region, the innate immune system serves as an important host defense system. We recently reported that peptide transporter 2 (PEPT2) has an essential role in the uptake of bacterial peptides and induction of innate immune response in alveolar epithelial cells. In this study, we aimed to clarify the effects of corticosteroids on PEPT2 function and PEPT2-dependent innate immune response. NCI-H441 (H441) cells were used as an in vitro model of human alveolar type II epithelial cells, and the effects of dexamethasone (DEX) and budesonide (BUD) on the transport function of PEPT2 and the innate immune response induced by bacterial peptides were examined. PEPT2 function, estimated by measuring β-alanyl-Nε-(7-amino-4-methyl-2-oxo-2H-1-benzopyran-3-acetyl)-L-lysine (β-Ala-Lys-AMCA) uptake in H441 cells, was suppressed by treatment with DEX and BUD in a concentration- and time-dependent manner. The suppression of PEPT2 function was partially recovered by a glucocorticoid receptor antagonist. The expression of PEPT2 and nucleotide-binding oligomerization domain 1 (NOD1) mRNAs was suppressed by treatment with DEX and BUD, while PEPT2 protein level was not changed by these treatment conditions. Additionally, the increased mRNA expression of interleukin (IL)-8 and the increased secretion of IL-8 into the culture medium induced by bacterial peptides were also suppressed by treatment with these corticosteroids. Taken together, these results clearly suggest that corticosteroids suppress PEPT2 function and bacterial peptide-induced innate immune response in alveolar epithelial cells. Therefore, PEPT2- and NOD1-dependent innate immune response induced by bacterial peptides in the lung alveolar region may be suppressed during the inhaled corticosteroid therapy.