Effects Of Total Flavonoids From Litsea Coreana Levl On Adjuvant-induced Arthritis And The Relationship Between ER Stress

Rheumatoid arthritis (RA), which is associated with systemic inflammatorydisorders, is a chronic, relapsing autoimmune disorder that is characterized by asymmetric polyarthritis with pain and swelling in multiple joints, synovial hyperplasia,erosion of cartilage and bones and infiltration of inflammatory cells. Many researchesrevealed that the activation of macrophages and inflammatory cytokines, such asTNF-α, played a crucial role in the processes of RA. Although there are lots of drugsshowing a good effect on RA, their side and toxic reactions call for more effective andsecure drugs.Litsea coreana Levl has been extensively used as herbal in southern China forhundreds of years. TFLC, an active component extracted from the leaves of Litseacoreana leve, possesses kinds of biological action, including hypoglycemic andhypolipidemic effects, significant anti-inflammatory activity and hepatoprotective.However, the detailed therapeutical mechanisms of TFLC have not been fullyunderstood.More and more researches found that endoplasmic reticulum stress (ERS) played a keyrole in the progress of inflammation and RA. The ERS is occurred when the structureor function of ER is disturbed by the accumulation of unfolded or misfolded protein,leading to the unfolded protein response (UPR). TFLC, an active component extractedfrom the fruit of Litsea coreana leve, possesses kinds of biological action, including hypoglycemic and hypolipidemic effects, significant anti-inflammatory activity andhepatoprotective. However, what relationship between its mechanism and ERS are stillnot understood. On the basis of our previous studies, the aim of the current work wasto observe the therapical effects on Complete Freund′s adjuvant-induced arthritis inrats. So CFA was used to induce AA in rats. TFLC (50,100,200mg/kg) wasadministered intragastrically. Adjuvant-induced arthritis was analyzed by body weight,secondary paw swelling and histopathology. TNF-α and IL-1β from blood serum weredetected by ELISA. RT-PCR was performed to compare CHOP、GRP78、XBP1、TNF–α expression in peritoneal macrophages. CHOP, GRP78, XBP1, TNF–α, p-JNK,p-P70S6K and p-Akt expression was evaluated by western blot. In vivo, our dataindicated that TFLC (100,200mg/kg, ig×10days) could significantly suppress weightreduction, secondary paw swelling and serum levels of TNF-α and IL-1β.Histopathological figures showed that TFLC treatment improved the morphologicchanges of articular cartilages and synovium. Analyzed by RT-PCR and westernblotting that proved TFLC suppress expression of78-KD glucose regulated protein(GRP78), X-box binding protein1(XBP1), mTOR complex1(mTORC1) and TNF-αin peritoneal macrophages of AA rats. These results suggest that TFLC is able toameliorate adjuvant-induced arthritis in a dose-dependent manner. The mechanism ofTNF-α inhibition may be related to suppress the IRE1-JNK pathway which isinteracted by mTORC1.