Interferon-γ-Dependent in vitro Model for the Putative Keratin 17 Autoimmune Loop in Psoriasis: Exploration of Pharmaco- and Gene-Therapeutic Effects

Abstract

In 1999, A.S. Gudmundsdottir et al. have envisaged an epitope on keratin 17 (K17) as a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, we now demonstrate that IFN-γ and to a less extent also TNF-α and TGF-α are able to induce K17 protein expression, in contrast to IL-1α, IL-1β, IL-6, IL-8 and IL-18. This supports our hypothesis of an existing proinflammatory cytokine/K17 autoimmune loop as a presumptive positive feedback mechanism driving psoriasis etiopathogenesis. K17 overexpression was now found to also coincide with suppression of keratinocyte proliferation, e.g. induced by NF-kappa B inhibitors (Bay 11-7082 and Bay 11-7085), and thereby correlated hyperapoptosis to be encountered in psoriatic epidermis. Acitretin as an established antipsoriatic drug and the tyrosine kinase inhibitor imatinib decreased, whereas hydrocortisone as well as dexamethasone increased the IFN-γ-induced K17 overexpression. The latter might be another mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment. Finally, we defined a K17-directed and effective antisense oligodesoxynucleotide which may hold promise for future gene-therapeutic approaches in psoriasis.

Effect of the Active Fraction of Flos Daturae on IFN-γ Induced Apoptosis in Immortalized Human Epidermal Keratinocyte Cells (HaCAT)

“…In other words, INF-not only inhibited the function of mitochondria, but also damaged the integrity of the cell membrane. These results were consistent with a previous study on IFN-induced cell injury [19]. Although AF-FD has been clinically used as a favorable psoriasis treatment, its mechanism of action was previously unknown.…”

“…In cell culture experiments, IFN-induced cell damage in HaCAT cells, derived from human skin, is one widely accepted cellular model of psoriasis. Böckelmann and coworkers consider this model reliable and credible in psoriasis research [19] and it was used in this investigation. MTT and LDH assays were implemented in this study to examine the effect of INF-on HaCAT cells.…”

“…Recent study [32] has recognized a K17/IFN-autoimmune loop as the etiopathogenesis mechanism in the process of psoriasis. IFN-, one of the key cytokines secreted by T cells, can induce the expression of K17, and K17 can, in return, stimulate the activation and proliferation of T cell, which forms the mutual promotion loop between K17 and T cells.…”

“…The sustained activation of T cells and the hyper-expression of K17 lead to an autoimmune reaction against K17, which may play a key role in the maintenance, increase, chronicity and recurrence of psoriasis. Thus it has been proposed [32] that the expression of K17 could be used as index of the disease severity and effects of treatment of psoriasis. In this study Western blotting was used to quantify the expression of K17.…”

“…In previous dermatopathologic research, it has been shown that IFN-can induce apoptosis in HaCAT cells in vitro [19] and increase the expression of K17, which makes it a globally acceptable mimic model of psoriasis [8,19]. In the present study, we evaluated the IFN-induced of apoptosis in HaCAT cells and the expression of K17, both in the presence and the absence of AF-FD.…”