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

Sci Rep. 2016 Nov 22;6:37751. doi: 10.1038/srep37751.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Bronchi / pathology
  • Cell Line
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Disease Models, Animal
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology*
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / enzymology*
  • Inflammation / pathology
  • MAP Kinase Signaling System* / drug effects
  • Male
  • Mice, Inbred BALB C
  • Phosphorylation / drug effects
  • Silymarin / pharmacology
  • Silymarin / therapeutic use*
  • Smoking / adverse effects*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cytokines
  • Silymarin
  • p38 Mitogen-Activated Protein Kinases