AS-703026 Inhibits LPS-Induced TNFα Production through MEK/ERK Dependent and Independent Mechanisms.

Ping Li,Xiaojing Zhao,Yonghong Wu,Manxiang Li,Xiaojuan Qiu,Xiaoyan Bai,Cong Cao

doi:10.1371/journal.pone.0137107

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by intense lung infiltrations of immune cells (macrophages and monocytes). Lipopolysaccharide (LPS) activates macrophages/monocytes, leading to production of tumor necrosis factor α (TNFα) and other cytokines, which cause subsequent lung damages. In the current study, our results demonstrated that AS-703026, a novel MEK/ERK inhibitor, suppressed LPS-induced TNFα mRNA expression and protein secretion in RAW 264.7 murine macrophages, and in murine bone marrow-derived macrophages (BMDMs). Meanwhile, TNFα production in LPS-stimulated COPD patents’ peripheral blood mononuclear cells (PBMCs) was also repressed by AS-703026. At the molecular level, we showed that AS-703026 blocked LPS-induced MEK/ERK activation in above macrophages/monocytes. However, restoring ERK activation in AS-703026-treated RAW 264.7 cells by introducing a constitutive-actively (CA)-ERK1 only partially reinstated LPS-mediated TNFα production. Meanwhile, AS-703026 could still inhibit TNFα response in ERK1/2-depleted (by shRNA) RAW 264.7 cells. Significantly, we found that AS-703026 inhibited LPS-induced nuclear factor κB (NFκB) activation in above macrophages and COPD patients’ PBMCs. In vivo, oral administration of AS-703026 inhibited LPS-induced TNFα production and endotoxin shock in BALB/c mice. Together, we show that AS-703026 in vitro inhibits LPS-induced TNFα production in macrophages/monocytes, and in vivo protects mice from LPS-induced endotoxin shock. Thus, it could be further studied as a useful anti-inflammatory therapy for COPD patients.

Highlights

Chronic obstructive pulmonary disease (COPD) is a major health problem in China and around the world
We aim to understand the potential effect of AS-703026, a novel MEK/ extracellular signal-regulated kinase (ERK) inhibitor [16,17], on LPS-induced tumor necrosis factor α (TNFα) production in macrophages
These results demonstrate that AS-703026 inhibits LPS-induced TNFα production in RAW 264.7 macrophages

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a major health problem in China and around the world. It is a progressive disorder characterized by massive airway inflammations [1,2,3]. COPD is accompanied with expiratory airflow obstruction, i.e. emphysema and chronic bronchitis [1,2,3]. Despite the fact that COPD’s incidence is increasing at an alarming rate, there has been no specific and/or effective therapies available to limit or prevent. AS-703026 Inhibits LPS-Induced TNFα Production the progression or airway destruction of COPD [1,2,3]. There is an urgent need to explore novel agents targeting this disease

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Results

Conclusion