The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-κB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection

Abstract

AbstractNeisseria gonorrhoeae(Ngo) is a Gram-negative pathogenic bacterium responsible for an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions betweenNgoand the mucosal epithelium, which induce a local inflammatory response. Here we analyzed the molecular mechanism involved in theNgo-induced induction of the proinflammatory cytokines tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-8. We identified the immediate early response transcription factor nuclear factor κB (NF-κB) as a key molecule for the induction of cytokine release.Ngo-induced activation of direct upstream signaling molecules was demonstrated for IκB kinase α and β (IKKα and IKKβ) by phosphorylation of IκBα as a substrate and IKK autophosphorylation. Using dominant negative cDNAs encoding kinase-dead IKKα, IKKβ, and NF-κB-inducing kinase (NIK),Ngo-induced NF-κB activity was significantly inhibited. Curcumin, the yellow pigment derived fromCurcuma longa, inhibited IKKα, IKKβ and NIK, indicating its strong potential to block NF-κB-mediated cytokine release and the innate immune response. In addition to the inhibition ofNgo-induced signaling, curcumin treatment of cells completely abolished the adherence of bacteria to cells in late infection, underlining the high potential of curcumin as an anti-microbial compound without cytotoxic side effects.