The IL-1 family in relation to psoriasis

Psoriasis is a common chronic inflammatory skin disease which can also affect the joints. Its pathogenesis is still to be fully elucidated and involves a wide range of inflammatory mediators, tissue and immune cells. At present, there is no treatment available to cure psoriasis. Although biologics have considerably improved the treatment of the most severe cases there is still a pressing clinical need to improve therapy for specific disease subtypes (e.g. pustular psoriasis) and the vast majority of patients suffering from psoriasis classified as mild to moderate. In particular, efficient and well tolerated topical approaches are lacking. This work has focused 1) on advancing our understanding of IL-36 cytokines which are recognised for their significance in pustular psoriasis, 2) on identifying endogenous disease limiting mediators such as IL-18 binding protein and how they could be manipulated in a therapeutic approach and 3) on IL-17 neutralising RNA aptamers as tools for topical therapy. Main results include the identification of biologic activity of processed and non-processed IL-36 members. N-terminal cleavage is required to increase activity of all IL-36 members. The protease responsible for IL-36RA processing was elucidated. Neutrophil proteases as well as kallikrein 7 can cleave pro-inflammatory IL-36 members. However, a second processing step seems necessary for full activation and the potentially responsible aminopeptidase remains to be identified. Secondly, it was found that human primary fibroblasts produce significant levels of IL-18BP, which controls pro-inflammatory function of IL-18. Endogenous IL-18BP can be induced by IL-27 which, when given in combination with hydrocortisone does not induce pro-inflammatory responses. Thirdly, an IL-17 specific aptamer was verified to block IL-17A activity in fibroblast and fibroblast Th17 co-cultures but not in keratinocyte cultures. Significant uptake of the RNA aptamer by keratinocytes was identified as potentially responsible for the lack of neutralising capacity

IL-27 Regulates IL-18 Binding Protein in Skin Resident Cells

IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48–72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts