Chronic hypoxia increases pro‐inflammatory TH17 cells via NFATc3‐induced interleukin 6 production in lung (1175.5)

Abstract

We have demonstrated that the adaptive immune system along with nuclear factor of activated T cells isoform c3 (NFATc3) contribute to chronic hypoxia (CH)‐induced pulmonary hypertension (PH). NFATc3 regulates IL‐6 expression in multiple cells types. Considering that IL‐6 contributes to hypoxic PH and is required for polarization of naïve CD4+ T helper cells to the TH17 subset, we hypothesized that NFATc3 drives IL‐6 expression in pulmonary arterial smooth muscle cells (PASMC) contributing to CH‐induced increases in lung TH17 cells. Since TH17 cells are implicated in several cardiovascular diseases, these cells may play an unexplored role in PH. In support of our hypothesis, we found that IL‐6 transcripts as determined by real‐time PCR were increased in cultured mouse PASMC in which NFAT was activated with ionomycin and phorbol 12‐myristate 13‐acetate. This response was prevented by the calcineurin/NFAT inhibitor cyclosporine A and is consistent with our previous report demonstrating that CH activates NFATc3 in PASMC. Furthermore, lung TH17 cells as determined by flow cytometry were increased in male C57BL/6 mice exposed to 5 days of CH (PB=380 mmHg) compared to normoxic mice. This response was prevented by i.p. administration of a selective NFAT inhibitor (A‐285222, AbbVie). Our data suggest that CH‐induced PASMC NFATc3 activation and subsequent IL‐6 production contribute to increases in lung TH17 cells.Grant Funding Source: Supported by T32 HL07736, R01HL088151, R01 HL088192, R01 AI097202