AS-703026 Inhibits LPS-Induced TNFα Production through MEK/ERK Dependent and Independent Mechanisms
Chronic obstructive pulmonary disease (COPD) is characterized by significant lung infiltration by immune cells, particularly macrophages and monocytes. These cells are activated by lipopolysaccharide (LPS), which triggers the production of tumor necrosis factor α (TNFα) and other cytokines, leading to lung damage. In this study, we demonstrate that AS-703026, a novel MEK/ERK inhibitor, effectively suppresses LPS-induced TNFα mRNA expression and protein secretion in RAW 264.7 murine macrophages as well as in murine bone marrow-derived macrophages (BMDMs). Furthermore, AS-703026 inhibited TNFα production in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from COPD patients. At the molecular level, AS-703026 blocked LPS-induced activation of the MEK/ERK pathway in these macrophages and monocytes. Restoring ERK activation in AS-703026-treated RAW 264.7 cells by introducing a constitutively active (CA)-ERK1 only partially reinstated LPS-induced TNFα production. Moreover, AS-703026 still inhibited TNFα response in RAW 264.7 cells depleted of ERK1/2 by shRNA. Importantly, AS-703026 was also found to inhibit LPS-induced nuclear factor κB (NFκB) activation in both macrophages and COPD patients’ PBMCs. In vivo, oral administration of AS-703026 reduced LPS-induced TNFα production and protected BALB/c mice from endotoxin shock. In conclusion, our findings show that AS-703026 inhibits LPS-induced TNFα production in macrophages/monocytes in vitro and protects mice from LPS-induced endotoxin shock in vivo, suggesting that AS-703026 could be a promising anti-inflammatory therapy for COPD patients.