The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

Abstract

IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasisassociated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, ␤-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.

The Serine Protease Marapsin Is Expressed in Stratified Squamous Epithelia and Is Up-regulated in the Hyperproliferative Epidermis of Psoriasis and Regenerating Wounds

“…Lactoferrin has been reported to have antimicrobial activity (14), which could be important for host defense in psoriatic lesions known to be highly resistant against bacterial, viral, and fungal infections. Of note, four kallikrein-related proteases (nomenclature according to Lundwall et al (15)), KLK6, KLK8, KLK10, and KLK13, were among the 15 most strongly up-regulated proteases (Table 2), consistent with other reports (11,16,17). RT-PCR experiments confirmed strong marapsin expression in psoriatic lesions and very weak or absent expression in normal and nonlesional skin (Fig.…”

“…Results for samples purified from three separate RHE tissues were normalized to the human RPL19 housekeeping gene and expressed as relative -fold change compared with T 0 using the comparative C t method according to the manufacturer's instructions. RNA samples from 48 h of treatment were also used to perform microarray analysis as described (11).…”

“…Reconstituted Human Epidermis (RHE) Tissue Model-Experiments with the EpiDerm RHE tissue model (MatTek) were carried out as described previously (11). Recombinant human cytokines and growth factors were from R&D Systems: IL-19, IL-20, IL-22, IL-24, IL-26, interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and transforming growth factor-␣ (TGF-␣).…”

Interleukin 20 protein locates to distinct mononuclear cells in psoriatic skin

“…Our results suggest that IL-20 is produced by keratinocytes and then possibly is taken up by papillary mononuclear cells. Hence, these data support that in psoriasis, keratinocyte derived IL-20 affects cells linked with the development of the pathological inflammation (16)(17)(18)(19).…”

Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

“…First, it prompts epithelial cells to secrete proinflammatory cytokines for leukocyte recruitment and activation (41,51). Second, it induces epithelial cell proliferation during wound healing (52,53). Third, it stimulates epithelial cells of skin, mucosa, and organ parenchyma to secrete host defense peptides (12,37,54).…”