IL-37 ameliorates experimental asthma by inhibiting IL-1

Abstract

Introduction: We have previously shown that production of the anti-inflammatory cytokine IL-37 is impaired in allergic asthmatics. Additionally, we could demonstrate that application of IL‑37 reduces experimental asthma in mice in an IL-18Rα- and SIGIRR-dependent fashion. Thus, supplementation of IL‑37 deficiency could be a novel approach towards asthma therapy. Aims and objectives: We aim to elucidate how IL-37 unfolds its regulatory effects on asthma pathogenesis. Methods: Immunohistochemical staining against IL-18Rα and SIGIRR was used to identify target cells for IL-37. Airway epithelial cells (AECs) were isolated via laser capture microdissection and examined by microarray-based gene expression analyses. Mononuclear cells (MNC) were isolated from sensitized mice and allergen-specifically activated. Air-Liquid Interface (ALI) cultures of AECs were stimulated with IL-1β. Wildtype and IL-1R1-deficient mice underwent induction of experimental asthma and were locally treated with IL-37. Results: Among others AECs, T helper 2 (Th2) cells, and dendritic cells were identified as target cells for IL-37. Gene array analysis of micro-dissected AECs revealed that IL-37 treatment of animals with experimental asthma lead to differential expression of >90 genes induced by IL-1 signaling. In line with this, IL-37 reduced IL-1β-induced expression of proinflammatory mediators in ALI cultures. Furthermore, IL-37 reduced production of IL-1β and Th2 cytokines in MNC. Finally, in contrast to WT mice IL‑37 had no therapeutic effect on experimental asthma in mice lacking IL-1R1. Conclusion: In conclusion, these findings indicate that IL-37 down-regulates allergic airway inflammation by inhibiting the proinflammatory activity of IL-1.