Interleukin-17 Targets Ppp6c for epidermal hyperplasia via NF-kappaB-dependent MicroRNA miR-31 induction (HUM7P.300)

Abstract

Abstract The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediator in this disease. However, it is unclear how IL-17 induces epidermal basal keratinocyte hyperproliferation in psoriasis. To explore the mechanism of IL-17 in epidermal hyperplasia in psoriasis, we focused on microRNA(s) induced by IL-17 as these small non-coding RNAs play an important role in regulation of cellular proliferation. Among all the microRNAs we screened, microRNA-31 (miR-31) is the only one extremely sensitive towards IL-17 for its induction in keratinocytes. Its expression in both the epidermis of lesional skin of human psoriasis patients and mouse psoriasis models is IL-17 inducible and NF-kappaB dependent. A causal relationship between IL-17-dependent miR-31 induction and basal keratinocyte hyperproliferation has been then established by constructing and analyzing epidermal conditional knockout of miR-31 (miR-31fl/fl/Keratin 5-Cre) engineering animals. A careful genomic analysis led us to realize that miR-31 targets protein phosphatase 6 (ppp6c), a negative regulator restricting G1 to S phase progression. As expected, ppp6c is suppressed by IL-17 through the miR-31 induction and is diminished in human psoriatic epidermis. We thus have uncovered a novel mechanism that helps explain how T helper (Th)-17 cells signal to basal keratinocytes for their hyperproliferation in psoriasis.