Regulation of interleukin-18 signalling in dendritic cells

• Main Author: Koutoulaki, Anna
• Published: Cardiff University 2008
• Subjects: 616.07
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.584504

This study demonstrates the mechanism of regulation of IL-18 function by the pro- and anti-inflammatory cytokines, TNFalpha and TGFbeta respectively. The importance of the antagonistic interaction between these two cytokines, to control IL-18 signalling, has been demonstrated using an in vitro model of dendritic precursor cells, which have the ability to produce IFNgamma and potentially mature upon stimulation with IL-18. The ability of TNFalpha to sensitise the cells and promote IL-18-induced IFNgamma production was suppressed in the presence of TGFbeta, in part via a mechanism of IL-18 receptor regulation. TNFalpha stimulation increased the levels of both mRNA and surface protein of IL-18 receptor, whereas the addition of TGFbeta resulted in 50% reduction of the surface expression of the receptor. Further work confirmed the counter effects of these cytokines on IL-18 signalling, through p38 MAPK activation and T-beta expression. The importance of TNFalpha and TGFbeta in controlling the maturation process of dendritic cells, by regulating their early IL-18-induced IFNgamma production, led to the hypothesis that blocking IL-18 could dampen Th1 immune response in chronic inflammatory conditions, through the regulation of dendritic cell maturation. Therefore, a soluble recombinant human heterodimeric receptor was generated and was confirmed to bind strongly to IL-18. Preliminary in vitro work showed that this soluble decoy receptor was active and able to suppress IL-18 function. Further studies to investigate the effects of this receptor in vivo may lead to the development of a potential anti-cytokine therapy for chronic inflammation.