Total tanshinones exhibits anti-inflammatory effects through blocking TLR4 dimerization via the MyD88 pathway

Abstract

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.

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

“…It is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in China Shi et al, 2019;Sun et al, 2019). Modern pharmaceutical studies showed that tanshinone also possess antiangiogenic, antioxidant, antibacterial, anti-inflammatory, and antitumor activities (Wang et al, 2016;Gao et al, 2017;Zhou et al, 2017). According to the chemical structure, tanshinones could be classified into different types, out of which tanshinone IIA (Tan IIA), dihydrotanshinone (DT), tanshinone I (Tan I), and cryptotanshinone (CT) generally considered most important (Hao et al, 2016a;Shi et al, 2016a).…”

Inhibition of TLR4/TRIF/IRF3 Signaling Pathway by Curcumin in Breast Cancer Cells

“…There has been a number of studies indicating the suppressive effect of different natural products (shinbaro3, curcumin, tanshinones, phloretin, xanthohumol, celastrol, garlic compounds etc.) on the different TLRs signaling (14,(23)(24)(25)(26). Additionally, several promising natural compounds (shinbaro3, curcumin, tanshinones) exert anti-inflammatory activities by suppressing TLR4/MyD88/NF-κB pathway.…”

An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid

“…Macrophages, the innate immune cells, play a predominant role in tissue inflammation response for eliminating invading pathogens ( Gao et al, 2017 ; Wu et al, 2017 ). Nevertheless, persistent or uncontrolled macrophage activation usually leads to the aberrant release of inflammatory cytokines and tissue damage ( Gao et al, 2017 ).…”

“…Macrophages, the innate immune cells, play a predominant role in tissue inflammation response for eliminating invading pathogens ( Gao et al, 2017 ; Wu et al, 2017 ). Nevertheless, persistent or uncontrolled macrophage activation usually leads to the aberrant release of inflammatory cytokines and tissue damage ( Gao et al, 2017 ). In recent decades, considerable investigations have shown that macrophage activation and subsequent inflammatory response contribute to the pathogenesis of a variety of serious diseases, including, but not limited to the tumor, cardiovascular disease, neurodegenerative disorder, obesity, and diabetes ( Ku et al, 2016 ; Mondal et al, 2016 ; Reyes-Farias et al, 2016 ; Liou et al, 2017 ).…”