IL1, IL6, and GMCSF are Downstream Mediators of IL17A that Promote Asymmetric Stem Cell Self-Renewal in Psoriasis

Interleukin 17A (IL17A) is a key cytokine in psoriasis and IL17A antibody therapy is an effective treatment for psoriasis. We previously showed that IL17A increases asymmetric stem cell self-renewal divisions in human keratinocytes and plays a role in the hyperproliferation of the epidermis observed in psoriasis. We hypothesized that downstream IL17A-induced keratinocyte cytokines were mediators of the increased asymmetric stem cell self-renewal divisions of psoriasis. We studied cytokines produced by keratinocytes after IL17A treatment and determined their effects on asymmetric stem cell self-renewal divisions in human keratinocytes in vitro, using sister pair analysis. Using ELISA, we showed that IL17A significantly increased the production of IL1α, IL6, IL8 and GMCSF by keratinocytes. IL1α, IL6, and GMCSF (but not TNFα and IL8) increased asymmetric stem cell self-renewal divisions in keratinocytes versus vehicle-treated keratinocytes (48.4±4.0% versus 36.4±3.8%, 51.2±1.1% versus 37.3±0.8%, and 47.8±2.7% versus 34.2±1.0%, P < 0.05, n=3, respectively). Increasing doses of IL1α antibody, IL6 antibody, and GMCSF antibody significantly inhibited IL17A-induced asymmetric stem cell self-renewal in a dose-dependent fashion. In summary, this study has identified key mediators involved in the increased asymmetric stem cell self-renewal divisions in psoriasis and may provide new avenues to finding treatments for the cutaneous manifestations of psoriasis. This study also confirms the important role of asymmetric stem cell self-renewal in inflammatory diseases and underscores the potential of manipulation of stem cell self-renewal as a therapeutic strategy.