Interleukin-1 interferes with the balance between proliferation and differentiation through insulin resistance in human keratinocytes – implications for psoriasis pathogenesis

Interleukin-1b (IL-b) not only plays a crucial role in the pathogenesis of psoriasis, but also induces insulin resistance in metabolic tissues. Therefore we asked whether IL-1b can confer similar effects in the skin that might contribute to the manifestation on the disease. In cultured keratinocytes we found that IL-1b renders keratinocytes resistant to insulin dependant activation of the PI3-K/PKB cascade, which is mediated by p38MAPK. Insulin also induces expression of cytokeratin 10, a marker of terminal differentiation, suggesting that insulin drives differentiation of healthy keratinocytes. This effect is blunted under chronic IL-1b treatment, resembling the inflammatory situation in psoriasis, where keratinocytes differentiation is abnormal and shifted towards hyperproliferation. Surprisingly we found that in the psoriatic plaque PKB/Akt is hyperactivated. This effect seems to be mediated by IL-1b, which in vitro can transiently activate the PKB cascade. This effect is not only mediated via PI3-K but also via p38MAPK, IKK and JNK. This leads to IL-1b dependent proliferation of kerytinocytes. We provide evidence that under healthy conditions insulin regulates the equilibrium between differentiation and proliferation of keratinocytes which is the prerequisite for proper formation of the epidermal layers. Under conditions of systemic inflammation such as psoriasis, high levels of IL-1b in the skin lead to blockade of differentiation by means of insulin resistance. At the same time IL-1b promotes hyperproliferation of keratinocytes. Both mechanisms contribute to the formation of the psoriatic plaque. Thus, controlling correct insulin signaling in the skin might represent a novel anti-psoriatic strategy.