4-O-methylascochlorin attenuates inflammatory responses induced by lipopolysaccharide in RAW 264.7 macrophages

Int Immunopharmacol. 2021 Jan:90:107184. doi: 10.1016/j.intimp.2020.107184. Epub 2020 Dec 11.

Abstract

Inflammation is implicated in various diseases, such as inflammatory bowel disease and cancer. Ascochlorin (ASC) and its derivatives have been shown to modulate inflammatory responses in many previous studies. However, the effects of 4-O-methylascochlorin (MAC), one of the ASC derivatives, on inflammatory responses have yet to be reported. In addition, the consequences of chemical modification of ASC on protein signaling and immunity have yet to be fully understood. The fourth carbon in MAC is methylated, which may result in modulation of immune response differently compared with ASC. Hence, we have investigated the role of MAC in inflammatory response induced by lipopolysaccharide in murine macrophage cells. Here, we found that MAC treatment decreased the inflammatory response by murine macrophages. When murine macrophages were treated with MAC, the transcription and translation of various pro-inflammatory indicators such as iNOS and COX-2 decreased. In addition, the ELISA results showed that the expression of TNF-α, IL-6, and IL-1β, which are pro-inflammatory cytokines, was successfully decreased by MAC. Such effects of MAC appear to be mediated via downregulation of MAPK signaling and the transactivational activity of NF-κB. Lipopolysaccharide upregulates MAPK protein phosphorylation and NF-κB translocation, which in turn enhances the transactivation of genes related to NF-κB. Such results of lipopolysaccharide were attenuated by MAC. Collectively, our results indicate that MAC alleviated the inflammatory responses induced by lipopolysaccharide in murine macrophages successfully by modulating MAPK signaling pathway and NF-κB-related genes. This study shows that MAC, similar to other ASC derivatives, can potentially be used therapeutically to reduce the harmful damage induced by prolonged inflammation. In addition, the structural differences between ASC and its derivatives as well as their effect on intracellular signaling will also be discussed.

Keywords: 4-O-Methylascochlorin; Ascochlorin-derivatives; Inflammation; RAW 264.7 Macrophage; TLR.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Inflammation Mediators / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipopolysaccharides / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation
  • RAW 264.7 Cells
  • Terpenes / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Terpenes
  • 4-O-methylascochlorin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases