Endocrine Abstracts

Retinoic-acid-inducible gene I (RIG-I) is a cytosolic receptor that sense RNA viruses, such as influenza, producing proinflammatory cytokines and type 1 interferons. In severe influenza infection, inappropriate immune response can allow influenza virus to proliferate, triggering hypercytokinemia that leads to tissue damage and potentially death of the host. Glucocorticoid hormones (GC) are clinically used to suppress hypercytokinemia. However, the use of GC is controversial during influenza infection and peripheral GC metabolism remains largely unknown. In peripheral tissues, GC action is controlled by pre-receptor GC metabolizing enzyme 11beta-hydroxysteroid dehydrogenase (11b-HSD). 11b-HSD1 predominantly converts inactive GC to active form within cells. Recent work has shown that 11b-HSD1 modulates immune and inflammatory response. Therefore, the aim of this study was to evaluate how peripheral GC metabolism affects RIG-I signaling during influenza infection.

Methods: 5’-Triphosphate modified RNA (3pRNA), the ligand for RIG-I, was transfected by lipofection in human lung A549 and HELF cells. Cells were cultured for 24 h in the presence or absence of 1 μM glucocorticoids (cortisone/cortisol) following 3pRNA treatment. The glucocorticoid receptor (GR) antagonist, RU486 added 30 min before GC. siRNA was transfected 48 h before 3pRNA treatment. Genes were measured by RT-qPCR.

Results: 3pRNA increased RIG-I downstream genes IFNb and IL6 mRNA levels, which were decreased by cortisol treatment. 11b-HSD1 was also increased by 3pRNA treatment and further increased by cortisol treatment. Accordingly, cortisone decreased IFNb and IL6 mRNA levels, although GILZ was not induced by cortisone treatment. 11b-HSD1 siRNA cancelled cortisone effects. Glucocorticoid receptor (GR) antagonist RU486 abolished GC reduction of IFNb and IL6 mRNA levels. Interestingly RU486 itself increased IFNb mRNA, indicating that GR can affect RIG-I signaling without exogenous GC.

Conclusion: Peripheral GC metabolism could selectively modulate RIG-I signaling during influenza infection. Further studies may address the mechanism of hypercytokinemia due to influenza infection.