GLP-2 Attenuates LPS-Induced Inflammation in BV-2 Cells by Inhibiting ERK1/2, JNK1/2 and NF-κB Signaling Pathways.

Nan Li,Ying-Jie Gao,Dian-Feng Liu,Ya-Long Zeng,Wei Wang,Wen-Zhi Ren,Ju-Xiong Liu,Xuan Yan,Bo-Wen Liu,Shou-Peng Fu,Su-Nan Li,Shi-Yao Xu

doi:10.3390/ijms17020190

Abstract

The pathogenesis of Parkinson’s disease (PD) often involves the over-activation of microglia. Over-activated microglia could produce several inflammatory mediators, which trigger excessive inflammation and ultimately cause dopaminergic neuron damage. Anti-inflammatory effects of glucagon-like peptide-2 (GLP-2) in the periphery have been shown. Nonetheless, it has not been illustrated in the brain. Thus, in this study, we aimed to understand the role of GLP-2 in microglia activation and to elucidate the underlying mechanisms. BV-2 cells were pretreated with GLP-2 and then stimulated by lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory enzymes (iNOS and COX-2) and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α); the related signaling pathways were evaluated by Western blotting. The rescue effect of GLP-2 on microglia-mediated neurotoxicity was also examined. The results showed that GLP-2 significantly reduced LPS-induced production of inducible nitric oxide synthase (iNOS), cyclooxygenase-s (COX-2), IL-1β, IL-6 and TNF-α. Blocking of Gαs by NF449 resulted in a loss of this anti-inflammatory effect in BV-2 cells. Analyses in signaling pathways demonstrated that GLP-2 reduced LPS-induced phosphorylation of ERK1/2, JNK1/2 and p65, while no effect was observed on p38 phosphorylation. In addition, GLP-2 could suppress microglia-mediated neurotoxicity. All results imply that GLP-2 inhibits LPS-induced microglia activation by collectively regulating ERK1/2, JNK1/2 and p65.

Highlights

Parkinson’s disease (PD) is a common chronic neurodegenerative disease in humans, affecting millions of people all over the world [1]
glucagon-like peptide-2 (GLP-2) Inhibits LPS-Induced Expression of inducible nitric oxide synthase (iNOS) and COX-2 Proteins and mRNA in BV-2 Cells iNOS and COX-2 are two important pro-inflammatory proteins correlated with LPS stimulation in microglia [13]
In order to investigate the effect of GLP-2 on the activation of LPS-stimulated BV-2 cells, BV-2 cells were pretreated with GLP-2 (10 ́9, 10 ́8, 10 ́7, 10 ́6 M) for 1 h and stimulated with LPS (1 μg/mL) for another 4 h. iNOS and COX-2 were examined by quantitative real-time PCR

Summary

Introduction

Parkinson’s disease (PD) is a common chronic neurodegenerative disease in humans, affecting millions of people all over the world [1]. The major character of PD’s neuropathology is the slow and progressive degeneration of dopaminergic neurons, which are located in the substantia nigra par compacta (SNpc) of the midbrain [2,3]. A large number of studies have shown that the involvement of neuro-inflammation processes in the degeneration of dopaminergic neurons is important [1,11,12,13]. Microglia are the main effector cells in the process of neuro-inflammation. Uncontrolled over-activation of microglia is a major component of neuro-inflammation [14]. It has been suggested that several pro-inflammation cytokines and/or pro-inflammatory enzymes, which are produced by over-activated microglia, are believed to contribute to neurodegenerative processes [15,16,17]. Inhibition of microglial over-activation would be a promising strategy to alleviate the further progression of PD

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