A novel synthetic oxazolidinone derivative BS-153 attenuated LPS-induced inflammation via inhibiting NF-κB/pkcθ signaling pathway

BS-153, a new derivative of Oxazolidinone, was firstly found having potent anti-inflammatory effects both in vitro and in vivo. Our study aimed to study its potential molecular mechanisms. Firstly, BS-153 significantly inhibited the expression levels of inflammatory mediators (iNOS and COX-2) and pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) on LPS-stimulated RAW264.7 cells in a dose-dependent manner. Subsequently, NF-κB nuclear translocation was blocked by 10 nM BS-153 after LPS-activated, and the phosphorylation of IκB, which could bind NF-κB and limit NF-κB nuclear translocation, was notably downregulated. The mechanistic investigation was followed the NF-κB-ikkα-TLR4/PKCθ pathway. The kinase panel screen and WB result revealed that BS-153 inhibited PKCθ phosphorylation on thr538 and ser643/676 site, and the expression of IL-17ɑ, instead of TLR4/MyD88. Similarly in vivo anti-inflammatory activity was assessed by LPS-stimulation and tail-amputation in zebrafish and the results indicated that macrophages migration and infiltration were significantly inhibited by BS-153. In addition, RT-PCR results discovered that BS-153 can reduce the level of TNF-α, IL-1b and COX-2. In summary, we established BS-153 and evaluated anti-inflammatory effect for the first time. The mechanism analysis showed that BS-153 possesses anti-inflammatory activities by inhibiting the phosphorylation of PKCθ, and then leading to the inactivation of NF-κB pathway. These findings implied that BS-153 is a potential candidate for the treatment of inflammatory-related diseases.

Anti-inflammatory; BS-153; NF-κB; PKCθ; TNF-α; Zebrafish.