Hypoxia-Inducible Factor 1 Alpha Potentiates Lipopolysaccharide-Induced Expression of IL-13 and IL-33 in Mast Cells Under Hypoxia

Abstract

Lipopolysaccharide (LPS) is an exacerbating factor for allergic airway inflammation at least partly due to the activation of mast cells (MCs). LPS stimulates MCs to express both pro-inflammatory and type 2 cytokines, among which interleukin (IL)-13 is essential for the generation of allergic diseases. LPS also induces the expression of “alarmins” such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) from various cell types including epithelial cells, and increased serum IL-33 levels were reported to correlate with disease severity of asthma. MCs reside in peripheral tissues where the oxygen concentration is significantly lower than that in the air and further decreased by inflammation and bronchoconstriction in asthma. However, the effects of hypoxia on LPS-induced cytokine expression in MCs have not been fully elucidated. Here we show that LPS induces Il4, Il6, Il13, Il33, Tnf, and Tslp mRNAs in MCs. Notably, hypoxia robustly enhanced expressions of Il13 and Il33, but not the other cytokines in LPS-stimulated MCs. We also found that this promotive effect is dependent on the presence of hypoxia-inducible factor (HIF) 1α protein. Our study will provide new insight on the role of MCs in the LPS-associated pathogenesis of allergic diseases.