Molecular insights into the differences in anti-inflammatory activities of green tea catechins on IL-1β signaling in rheumatoid arthritis synovial fibroblasts

Toxicol Appl Pharmacol. 2017 Aug 15;329:112-120. doi: 10.1016/j.taap.2017.05.016. Epub 2017 May 19.

Abstract

In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectiveness could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea.

Keywords: Catechins; EGC; EGCG; Green tea; Inflammation; Rheumatoid arthritis.

MeSH terms

  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / isolation & purification
  • Anti-Inflammatory Agents / pharmacology*
  • Antirheumatic Agents / chemistry
  • Antirheumatic Agents / isolation & purification
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Catalytic Domain
  • Catechin / analogs & derivatives*
  • Catechin / chemistry
  • Catechin / isolation & purification
  • Catechin / pharmacology
  • Cells, Cultured
  • Cyclooxygenase 2 Inhibitors / isolation & purification
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Fibroblasts / drug effects*
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Humans
  • Interleukin-1beta / pharmacology*
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / chemistry
  • MAP Kinase Kinase Kinases / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Molecular Docking Simulation
  • NF-kappa B / metabolism
  • Phosphorylation
  • Phytotherapy
  • Plants, Medicinal
  • Protein Binding
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-jun / metabolism
  • Signal Transduction / drug effects*
  • Synovial Membrane / drug effects*
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism
  • Tea / chemistry*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antirheumatic Agents
  • CXCL8 protein, human
  • Cyclooxygenase 2 Inhibitors
  • IL1B protein, human
  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-jun
  • Tea
  • Catechin
  • epigallocatechin gallate
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • gallocatechol