In Vitro and In Situ Expression of IL-23 by Keratinocytes in Healthy Skin and Psoriasis Lesions: Enhanced Expression in Psoriatic Skin

Abstract

Keratinocytes contribute to cutaneous immune responses through the expression of cytokines. We investigated whether human keratinocytes can express IL-23, a newly defined IFN-γ-inducing cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12. Cultured keratinocytes from normal and lesional psoriatic skin were found to express constitutively mRNA for both subunits of IL-23. Low but significant levels of the heterodimeric IL-23 protein could be detected in cell lysates and supernatants from stimulated keratinocytes by immunoblotting and ELISA. Functional analysis showed that these low levels of keratinocyte-derived IL-23 were sufficient to enhance the IFN-γ production by memory T cells. Immunostaining of skin sections confirmed expression of both subunits of IL-23 by keratinocytes in situ and also revealed expression of this cytokine in the dermal compartment. IL-23 expression was significantly higher in psoriatic lesional skin, compared with normal and psoriatic nonlesional skin. The immunostained preparations of cultured cells and IL-23 levels in culture supernatants did not show any difference between normal and psoriatic keratinocytes indicating no intrinsic aberration of IL-23 expression in keratinocytes from psoriatic skin. Double staining of cytospin preparations demonstrated that IL-23 p19 is also expressed by epidermal Langerhans cells, dermal dendritic cells, and macrophages. Psoriasis is a chronic inflammatory skin disease mediated by IFN-γ-expressing type 1 memory T cells. As IL-23 is important to activate memory T cells to produce IFN-γ, its augmented expression of IL-23 by keratinocytes and cutaneous APC may contribute to the perpetuation of the inflammation process in this disease.

New insights of T cells in the pathogenesis of psoriasis

“…[49][50][51][52] Moreover, psoriatic skin lesions also contain high mRNA and protein levels of IL-23 compared with non-lesional and normal skin and IL-23 has been found to be produced mainly by the activated macrophages and DCs. [53][54][55] Intradermal injection of IL-23 or IL-21 in mice can stimulate keratinocytes proliferation and cause epidermal hyperplasia (acanthosis), which is one of the most significant features in human psoriasis. 51,56 Further studies demonstrated that IL-22, IL-17A as well as CC chemokine receptor (CCR) 6 are all required for IL-23-induced psoriasis-like skin inflammation.…”

IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine

“…We did not observe a reduction in IL-23p19 mRNA expression in epidermal and whole PP skin after IL-4 stimulation. However, this corresponds with a previous study stating that psoriatic KC lack intrinsic aberrant expression of IL-23, and therefore, IL-23 may not be further reduced by IL-4 in culture conditions (52). In addition, IL-1b and IL-6 are necessary for Th17 induction by DC (6,10).…”

“…IL-23p19 is increased in PP and can be produced by KC, but DC are the main source (40,51,52). Reports showed that IL-23 production by DC is inhibited by IL-4 and that downmodulation of DC and IL-23p19 is an early effect during psoriasis treatment (20,26).…”

Psoriasis: Ustekinumab and Other Biologics in the Pipeline

“…IL-23, then, subsequently may provide a stimulus for the proliferation of the Th17 cells [22,23]. Dendritic cells secrete IL-23-along with IL-12, another key cytokine for Th1 differentiation-but IL-23 also can be produced by keratinocytes and non-dendritic, antigenpresenting cells [24][25][26]. IL-23, a heterodimeric cytokine in the IL-12 family, is composed of the p19 and p40 subunits that can then bind to the receptor made up of IL-12Rβ1 and IL-23R [27].…”