Flavonoids from Litsea coreana decreases TNF-α secretion from peritoneal macrophages in adjuvant-induced arthritis rats via UPR pathway

Am J Chin Med. 2014;42(4):905-19. doi: 10.1142/S0192415X14500578.


Macrophages play a crucial role in rheumatoid arthritis (RA). Their activation is the initial step of RA. This study was designed to detect the effects of total flavonoids from Litsea coreana Levl. (TFLC) on the complete Freund's adjuvant-induced (CFA-induced) arthritis (AA) in rats and to explore whether inflammatory cytokines were induced by the IRE1/mTORC1/TNF-α-dependant mechanism in peritoneal macrophages. In vivo, our data indicated that TFLC (100, 200 mg/kg, i.g. × 10 days) could significantly suppress secondary paw swelling and serum levels of TNF-α and IL-1β. Histopathological figures showed that TFLC treatment improved the morphologic changes of articular cartilages and synovium. Results of RT-PCR and western blotting demonstrated that TFLC suppressed expression of 78-KD glucose regulated protein (GRP78), X-box binding protein 1 (XBP1), mTOR complex 1 (mTORC1) and TNF-α in peritoneal macrophages of AA rats. Collectively, these results indicate that TFLC is able to ameliorate adjuvant-induced arthritis in a dose-dependent manner by suppressing the IRE1/mTORC1/TNF-α-regulated inflammatory response initiated in peritoneal macrophages.

Keywords: Arthritis; Peritoneal Macrophage; TNF-α; Total Flavonoids from Litsea coreana Levl. (TFLC); Unfolded Protein Response (UPR); mTOR Complexes 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / immunology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Flavonoids / isolation & purification
  • Flavonoids / pharmacology*
  • Flavonoids / therapeutic use*
  • Inflammation Mediators / metabolism
  • Interleukin-1beta / metabolism
  • Litsea / chemistry*
  • Macrophage Activation / immunology*
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / metabolism
  • Multiprotein Complexes / metabolism
  • Phytotherapy*
  • Plant Leaves
  • Protein Serine-Threonine Kinases / metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / genetics*


  • Flavonoids
  • Inflammation Mediators
  • Interleukin-1beta
  • Membrane Proteins
  • Multiprotein Complexes
  • Tumor Necrosis Factor-alpha
  • Ern2 protein, rat
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases