Two novel IL-1 family members, IL-1δ and IL-1ε, function as an antagonist and agonist of NF-κB activation through the orphan IL-1 receptor-related protein 2

IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1 delta and IL-1 epsilon. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1 delta and epsilon. Levels of keratinocyte IL-1 delta are similar to 10-fold higher than those of IL-1 epsilon. In vitro stimulation of keratinocytes with IL-1 beta /TNF-alpha significantly up-regulates the expression of IL-1 epsilon mRNA, and to a lesser extent of IL-1 delta mRNA. In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1 delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1 alpha and beta or IL-1 delta. However, IL-1 epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1 delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1 epsilon response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1 delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1 alpha beta /receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.