LSC - 2017 - IL-1R1 but not IL-18Rbeta or IL-18BP contribute to the beneficial effects of IL-37 on experimental asthma

Abstract

Introduction: The recent identified IL-1-family member Interleukin (IL-) 37 has been described as a negative regulator of innate immunity. Since the production of IL-37 is impaired in allergic asthmatics, it is likely that IL 37 is involved in asthma pathogenesis. We have previously shown that IL-37 ameliorates experimental asthma via a mechanism that requires IL 18 receptor (R) a and single Ig IL-1-related receptor (SIGIRR). Aims and objectives: This study is aimed to elucidate the role of other IL-1 family members in IL-37 signaling. Methods: Experimental asthma was induced in mice deficient in IL-18Rs, IL-18 binding protein (BP) or IL-1R1. IL 37 was applied intra-trachealy during allergen challenge. Airway inflammation, mucus production and airway hyperresponsiveness (AHR) were assessed and compared to healthy and asthmatic control groups. Results: Application of IL-37 reduced the level of pro-inflammatory cytokines, allergic airway inflammation and AHR in IL-18Rs-deficient as well as IL-18BP-deficient mice, which was comparable to the effects seen in wildtype animals. In contrast, IL-37 treatment of IL-1R1-deficient mice had no effect on allergic airway inflammation or the level of proinflammatory cytokines. Conclusion: Our studies demonstrate that IL-37 requires IL-18Ra and SIGIRR as well as IL-1R1 to ameliorate experimental asthma in mice, but not IL-18Rs or IL-18BP. This indicates that IL-37 does not use the entire IL-18 signaling complex, but rather forms a complex with IL-18Ra and SIGIRR to inhibit signaling of proinflammatory cytokines like IL-1.