cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

Abstract

We examine the effects of IL18 on monocytes by performing microarray experiments using cell line KG1. Based on sensitivity to IL18, we identified three functionally distinct gene expression clusters (EC). We see little proinflammatory gene induction at low IL18 concentrations, but instead observe induction of diverse NFkB signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NFkB. At the highest IL18 concentration, we observe a third gene cluster containing the proapoptotic Fas gene among others. Clustering of IL18-responsive genes based on cis-elements in their promoters agreed well with the ECs. We conclude that IL18 produces a dosedependent transcriptional response that can in part be attributed to the composition of cis-elements in the promoters of IL18-responsive genes. These results also support a model for regulatory mechanisms that prevent spurious immune response due to weak cytokine fluctuations and a separate mechanism enabling induction of proinflammatory functions by higher levels of cytokine.

A comprehensive pathway map of IL-18-mediated signalling

“…In addition to the activation and inhibition of signaling events in different cell types, the downstream signaling proteins that are induced by IL‐18 also varies with cell types. IL‐18 induces the activation and nuclear translocation of cytosolic NFκB1 proteins in normal human epidermal melanocytes (NHEM), cortical neurons, myelomonocytic cells, cardiac microvascular endothelial cells (EC) which results in the production and release of MIP1‐alpha and ‐beta, MIP2‐alpha and ‐beta, and IL‐8 (Leyfer et al 2004; Zabalgoitia et al 2008; Zhou et al 2013). In chondrocytes, embryonic stem (ES) cells, human cardiac microvascular endothelial cells, and human alveolar basal epithelial cells, IL‐18 induces the expression of IL‐6 and IL‐8.…”

“…Following the complex formation, the classical Myddosome complex (MYD88/ IRAK/TRAF6) is recruited (Kojima et al 1998), and the recruitment of MYD88 likely involves TRAM, a sorting adaptor known for its role in TLR signaling (Ohnishi et al 2012). It is presumed that similar to IL-1/IL1R signaling, IL-18 mediated TRAF6 ubiquitination of IκBα kinase (CHUK) results in its degradation and concomitant activation and release of NFκB that translocates to the nucleus to induce transcription of inflammatory genes, including proinflammatory cytokines, chemokines, and adhesion molecules (Chandrasekar et al 2004(Chandrasekar et al , 2006b(Chandrasekar et al , 2008Doffinger et al 2001;Finotto et al 2004;Lee et al 2004;Leyfer et al 2004;Reddy et al 2010Reddy et al , 2011Zabalgoitia et al 2008). IL-18 also activates the MAPK cascade to induce STAT3 activation, IFNγ production and resultant cytotoxic activity in NK cells (Kalina et al 2000).…”