Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

Abstract

Cigarette smoke (CS) is a major risk of chronic obstructive pulmonary disease (COPD), contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS-exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract (CSE)-induced inflammation using human bronchial epithelial cells. Silymarin significantly suppressed autophagy activation and the activity of ERK/p38 mitogen-activated protein kinase (MAPK) pathway in Beas-2B cells. We also observed that inhibiting the activity of ERK with specific inhibitor U0126 led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Moreover, silymarin attenuated CSE-induced upregulation of inflammatory cytokines TNF-α, IL-6 and IL-8 which could also be dampened by ERK/p38 MAPK inhibitors and siRNAs for Beclin-1 and Atg5. Finally, we validated decreased levels of both autophagy and inflammatory cytokines (TNF-α and KC) in CS-exposed mice after silymarin treatment. The present research has demonstrated that CSE-induced autophagy in bronchial epithelia, in synergism with ERK MAPK pathway, may initiate and exaggerate airway inflammation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases.

Azelaic Acid Induces Mitochondrial Biogenesis in Skeletal Muscle by Activation of Olfactory Receptor 544

“…Activation of ERK1/2 subsequently triggers phosphorylation of a number of downstream targets that regulate the autophagy pathway. ERK1/2 phosphorylation has been shown to enhance autophagy in Silymarin-treated Beas-2B cells or mediate phosphorylated Bcl-2 regulated starvation-induced autophagy (Tang et al, 2010;Li et al, 2016). It has been shown that MEK-ERK inhibitors, such as U0126, or amino acids can inhibit autophagy (Pattingre et al, 2003;Tang et al, 2010).…”

Differential expression of heat shock proteins and activation of mitogen‐activated protein kinases in A549 alveolar epithelial cells exposed to cigarette smoke extract

“…() showed that CSE‐induced apoptosis in BEAS‐2B cells was regulated by the ASK‐1/p38 signalling cascade. Another study on BEAS‐2B cells showed that CSE‐induced upregulation of inflammatory cytokines was dependent on the ERK/p38 signalling pathway (Li D et al., ). In contrast to these studies, Li, Xu, and Shen () demonstrated that CSE does not activate MAPKs and does not affect the release of IL‐8 in primary epithelial cells of the respiratory tract.…”

“…Lin et al (2014) showed that CSE-induced apoptosis in BEAS-2B cells was regulated by the ASK-1/p38 signalling cascade. Another study on BEAS-2B cells showed that CSE-induced upregulation of inflammatory cytokines was dependent on the ERK/p38 signalling pathway (Li D et al, 2016). In contrast to these studies, Li, Xu, and Shen (2007) Induction of apoptosis through the activation of FasL-p38/JNK-Jun signalling pathway in lungs of smoking rats was demonstrated (Kuo et al, 2005;Wu, Lin, Yan, Wu, & Wang, 2006).…”

β-Arrestin2 Inhibits Expression of Inflammatory Cytokines in BEAS-2B Lung Epithelial Cells Treated with Cigarette Smoke Condensate via Inhibition of Autophagy

“…For example, in a previous study published by our group, we found that the levels of pulmonary autophagy in a COPD mouse model were increased, and that the levels of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid were also increased [27]. In another study, Li and co-workers found that silymarin reduced airway inflammation induced by cigarette smoke by inhibiting autophagy and the ERK/p38 MAPK pathway [28].…”