Neutralization of both IL-1 alpha/IL-1 beta plays a major role in suppressing combined cigarette smoke/virus-induced pulmonary inflammation in mice

摘要

Smoking is an important risk factor for the development of chronic obstructive pulmonary disease (COPD) and viral infections are believed to be major triggers of exacerbations, which periodically lead to a worsening of symptoms. The pro-inflammatory IL-1 family members IL-l alpha and IL-1 beta are increased in COPD patients and might contribute to disease pathology. We investigated whether individual or combined inhibition of these cytokines reduced lung inflammation in cigarette smoke (CS)-exposed and H1N1-infected BALB/c mice. Animals were treated with individual or combined antibodies (Abs) directed against IL-1 alpha, IL-1 beta or IL-1R1. Cells in BAL fluid and cytokines/chemokines in lung homogenate were determined. The viral load was, investigated. Blocking IL-1 alpha had significant suppressive effects on total cells, neutrophils, and macrophages. Furthermore, it reduced KC levels significantly. Blocking of IL-1 beta did not provide significant activity. In primary human bronchial epithelial air-liquid-interface cell cultures infected with H1N1, IL-l alpha Abs but not 1L-1 beta Abs reduced levels of TNF-alpha and IL-6. Concomitant usage of Abs against IL-1 alpha/IL-1 beta revealed strong effects in vivo and reduced total cells, neutrophils and macrophages. Additionally, levels of ICC, IL-6, TNF-alpha, MCP-1, M1P-1 alpha and MIP-1 beta were significantly reduced and ICAM-1 and MUC5 A/C mRNA expression was attenuated. The viral load decreased significantly upon combined IL-1 alpha/IL-1 beta Ab treatment. Blocking the IL-1R1 provided significant effects on total cells, neutrophils and macrophages but was inferior compared to inhibiting both its soluble ligands IL-1 alpha/IL-1 beta. Our results suggest that combined inhibition of IL-l alpha/IL-1 beta might be beneficial to reduce CS/H1N1-induced airway inflammation. Moreover, combined targeting of both IL-1 alpha-IL-1 beta might be more efficient compared to individual neutralization IL-l alpha or IL-1 beta or inhibition of the IL-1R1. (C) 2017 The Authors. Published by Elsevier Ltd.