Sesquiterpene lactones inhibit Yersinia invasin protein-induced IL-8 and MCP-1 production in epithelial cells

Enteric Yersinia bacteria trigger transcription and secretion of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in epithelial cells. Both chemokines are controlled by NF-κB. The NF-κB-binding site in the IL-8 promoter preferentially binds Rel p65/p65 homodimers and p50/p65 heterodimers while the NF-κB-binding motifs of the MCP-1 promoter preferably bind p50/p65 heterodimers and p50/p50 homodimers. Sesquiterpene lactones inhibit the transcription factor NF-κB by alkylating the p65 subunit. In this study we investigated the inhibitory effects of sesquiterpene lactones and the NF-κB inhibitor SN50 on NF-κB p50 and p65 subunits in Yersinia-triggered IL-8 and MCP-1 production. The sesquiterpene lactones blocked Yersinia-triggered IL-8 and MCP-1 production in a dose-dependent manner. In contrast, SN50 inhibited IL-8 production at high concentrations whereas it diminished the amount of secreted MCP-1 significantly already at low concentrations. By means of electrophoretic mobility shift assays we demonstrate that sesquiterpene lactones inhibit Yersinia-triggered activation of NF-κB by inhibiting Rel p65, but not Rel p50. Our results also demonstrate that SN50 is useful for inhibition of nuclear translocation of the NF-κB p50 subunit but cannot be considered a general NF-κB inhibitor.