Amelioration of TPA-induced skin inflammation by the leaf extract of Vernonia amygdalina involves ERK/STAT3 (Ser727) signaling inhibition

Jia Ying Wu, Jian Hua Xie, Ying Jie Chen, Xiu Qiong Fu, Rui Jun Wang, Yu Yi Deng, Shuo Wang, Hai Xia Yu, Chun Liang, Zhi Ling Yu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Uncontrolled inflammation causes health problems. Extracellular signal-regulated kinase (ERK) phosphorylates signal transducer and activator of transcription 3 (STAT3) at Ser727, resulting in inflammation. The leaf of Vernonia amygdalina (VA) is a medicinal herb for managing inflammation-associated diseases. Oral administration or topical application of VA leaf extract exerts anti-inflammatory effects in rat models. However, the anti-inflammatory mechanisms of the herb are not fully understood. 

Purpose
In this study, we aimed to investigate the involvement of ERK/STAT3 (Ser727) signaling in the anti-inflammatory effects of an ethanolic extract of VA leaves. 

Study design and methods
Extracts of VA leaves were prepared with different concentrations of ethanol. A LPS-stimulated RAW264.7 cell model was used for in vitro assays, and a TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ear edema mouse model was employed for in vivo assays. The 95% ethanol extract of VA leaves (VAE) exerted the strongest inhibitory effect on nitric oxide (NO) production in LPS-stimulated macrophages; thus it was selected for use in this study. Hematoxylin and eosin (H&E) staining was used to examine pathological conditions of mouse ear tissues. Griess reagent was employed to examine NO generation in cell cultures. Immunoblotting and ELISA were used to examine protein levels, and RT-qPCR was employed to examine mRNA levels.

Results
Topical application of VAE ameliorated mouse ear edema induced by TPA. VAE suppressed the phosphorylation of ERK (Thr202/Tyr204) and STAT3 (Ser727); and decreased protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) in the mouse ear tissues and in LPS-stimulated RAW 264.7 cells. VAE also inhibited NO production, and lowered mRNA levels of IL-6, IL-1β and TNF-α in the macrophages. 

Conclusions
VAE ameliorates TPA-induced mouse ear edema. Suppression of ERK/STAT3 (Ser727) signaling is involved in VAE's anti-inflammatory effects. These novel data provide further pharmacological justifications for the medicinal use of VA in treating inflammation-associated diseases, and lay the groundwork for developing VAE into a new anti-inflammatory agent.
Original languageEnglish
Article number154194
Number of pages7
JournalPhytomedicine
Volume102
Early online date23 May 2022
DOIs
Publication statusPublished - 20 Jul 2022

Scopus Subject Areas

  • Drug Discovery
  • Molecular Medicine
  • Complementary and alternative medicine
  • Pharmacology
  • Pharmaceutical Science

User-Defined Keywords

  • Acute inflammation
  • ERK
  • STAT3
  • TPA
  • Vernonia amygdalina
  • COX-2, cyclooxygenase-2
  • ERK, extracellular signal-regulated kinase IL, interleukin
  • NO, nitric oxide
  • iNOS, inducible nitric oxide synthase
  • MAPK, mitogen-activated protein kinase
  • STAT3, signal transducer and activator of transcription 3
  • TNF-α, tumor necrosis factor-α
  • VA, Vernonia amygdalina Del.
  • VAE, the 95% ethanol extract of VA leaves

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