Celastrol attenuates interleukin-8 release from LPS-activated human monocytes and monocyte-derived macrophages by inhibiting the NF-B signalling pathway

Interleukin-8 (IL-8), a potent neutrophil chemotactic factor, plays a critical role during inflammation. IL-8 is produced primarily by several immune cell types upon lipopolysaccharide (LPS) stimulation by activating the nuclear factor-KB (NF-KB) signalling pathway. NF-KB is an important transcription factor implicated in the inflammatory response, and the NF-KB signalling pathway is a potential target for inhibition by anti-inflammatory compounds. Celastrol has been shown to have therapeutic potential in treating many inflammatory diseases; however, there is little information on its ability to attenuate IL-8 production in human monocytes and macrophages. Here, we determined the effects of celastrol on LPS-induced IL-8 release and its molecular mechanism. Celastrol treatment significantly reduced IL-8 release from LPS-activated human monocytes and monocyte-derived macrophages with IC50 values of 3.13 +/- 0.03 mu M and 3.18 +/- 0.05 mu M, respectively. Additionally, the inhibitory effect of celastrol on the production of IL-8 was related to the modulation of IL-8 mRNA levels. Pre-treatment with celastrol significantly inhibited IKK, IKBa, and p65 phosphorylation and also prevented IKBa degradation due to LPS activation. Collectively, these results demonstrate that celastrol attenuates the release of IL-8 from LPS-activated human monocytes and monocyte-derived macrophages and suggest that inhibition of NF-KB signalling activation is likely a mechanism for the attenuation. This anti-inflammatory effect further highlights the therapeutic potential of celastrol.