Key cytokines in the pathogenesis of psoriasis induce insulin resistance at the endothelial cell level

Psoriasis is a common, chronic inflammatory skin disease which is characterized by red scaly plaques. Patients suffering from severe psoriasis have a higher incidence of diabetes and coronary atherosclerosis. The common denominator of these co-morbidities is insulin resistance. We have previously shown that the psoriatic cytokine milieu not only induces systemic insulin resistance, but epidermal insulin resistance represents a pathomechanism during the plaque development. Pathomechanisms in endothelial cells leading to the manifestation of the cutaneous phenotype on one hand and to the co-morbidities on the other hand are not sufficiently investigated. Due to the similarities between a psoriatic and an atherosclerotic plaque, we hypothesize that the underlying mechanism and pathways that are known to play a role in the development of atherosclerosis also contribute to the pathogenesis of psoriasis and its co-morbidities. Measuring insulin-dependent PKB phosphorylation, we could show that IL-17, IL-22, IL-23 and TNFα induce insulin resistance in primary endothelial cells (HUVEC and HDBEC [human dermal blood endothelial cells]) as well as in endothelial cell lines (HBMEC and HPEC-A2). Under normal conditions insulin counteracts the cytokine-dependent surface expression of ICAM-1, which is impaired under conditions of insulin resistance. Therefore insulin is not only cardio protective, but as well anti-inflammatory. We assume that these changes at the endothelial wall contribute to the pathogenesis of psoriasis and its co-morbidities. These novel insights can furthermore lead to novel therapeutic approaches that target the dermal and cardiovascular effects of the psoriatic inflammation.