A Novel Role for IκBζ in the Regulation of IFNγ Production

I kappa b zeta is a novel member of the I kappa B family of NF kappa B regulators, which modulates NF kappa B activity in the nucleus, rather than controlling its nuclear translocation. I kappa B zeta is specifically induced by IL-1 beta and several TLR ligands and positively regulates NF kappa B-mediated transcription of genes such as IL-6 and NGAL as an NF kappa B binding co-factor. We recently reported that the IL-1 family cytokines, IL-1 beta and IL-18, strongly synergize with TNF alpha for IFN gamma production in KG-1 cells, whereas the same cytokines alone have minimal effects on IFN gamma production. Given the striking similarities between the IL-1R and IL-18R signaling pathways we hypothesized that a common signaling event or gene product downstream of these receptors is responsible for the observed synergy. We investigated I kappa b zeta protein expression in KG-1 cells upon stimulation with IL-1 beta, IL-18 and TNF alpha. Our results demonstrated that IL-18, as well as IL-1 beta, induced moderate I kappa b zeta expression in KG-1 cells. However, TNF alpha synergized with IL-1 beta and IL-18, whereas by itself it had a minimal effect on I kappa b zeta expression. NFkB inhibition resulted in decreased IL-1 beta/IL-18/TNF alpha-stimulated IFN gamma release. Moreover, silencing of I kappa b zeta expression led to a specific decrease in IFN gamma production. Overall, our data suggests that I kappa b zeta positively regulates NF kappa B-mediated IFN gamma production in KG-1 cells.