Total tanshinones exhibits anti-inflammatory effects through blocking TLR4 dimerization via the MyD88 pathway.
Hongwei GaoXin LiuWen SunNaixin KangYanli LiuShilin YangQiong-Ming XuChunming WangXiuping ChenPublished in: Cell death & disease (2017)
Tanshinones belong to a group of lipophilic constituents of Salvia miltiorrhiza Bunge (Danshen), which is widely used in traditional Chinese medicine. A deluge of studies demonstrated that tanshinones exert anti-inflammatory effects, but the underlying mechanisms remain unclear to date. This study investigated the anti-inflammatory effects and mechanisms of total tanshinones (TTN). TTN suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the secretion of TNF-α, IL-6, and IL-1β in RAW264.7 cells, bone marrow-derived macrophages, and THP-1 cells. TTN attenuated the LPS-induced transcriptional activity of NF-κB and decreased IκB-α and IKK phosphorylation and NF-κB/p65 nuclear translocation. Furthermore, TTN inhibited the LPS-induced transcriptional activity of AP-1, which was induced by the reduction of JNK1/2, ERK1/2, and p38MAPK phosphorylation. TTN blocked LPS-induced Toll-like receptor 4 (TLR4) dimerization, which consequently decreased MyD88 recruitment and TAK1 phosphorylation. In addition, TTN pretreatment effectively inhibited xylene-induced ear edema and LPS-induced septic death and improved LPS-induced acute kidney injury in mice. TTN exerts anti-inflammatory effects in vitro and in vivo by blocking TLR4 dimerization to activate MyD88-TAK1-NF-κB/MAPK signaling cascades, which provide the molecular basis of the anti-inflammatory effect of Danshen and suggest that TTN is a potential agent for the treatment of inflammatory diseases.
Keyphrases
- lps induced
- toll like receptor
- inflammatory response
- nitric oxide synthase
- nuclear factor
- induced apoptosis
- signaling pathway
- immune response
- cell cycle arrest
- transcription factor
- oxidative stress
- gene expression
- nitric oxide
- rheumatoid arthritis
- anti inflammatory
- pi k akt
- poor prognosis
- type diabetes
- acute kidney injury
- mesenchymal stem cells
- cell death
- protein kinase
- metabolic syndrome
- insulin resistance
- replacement therapy
- endothelial cells
- binding protein
- skeletal muscle
- risk assessment
- human health