Inter-Regulation of Th17 Cytokines and the IL-36 Cytokines In Vitro and In Vivo: Implications in Psoriasis Pathogenesis

Abstract

Accumulating evidence indicates that IL-1 family members and Th17 cytokines have a pathogenic role in psoriasis. We investigated the regulatory interactions of the IL-1-like IL-36 cytokine family and the Th17 cytokines in the context of skin inflammation. We observed increased gene expression of all three IL-36 cytokines in a Th17-dominant psoriasis-like animal model. The induction was downregulated by neutralizing IL-22. Expression of the IL-36s was also induced in cultured primary human keratinocytes (KC) by IL-17A and tumor necrosis factor (TNF)-α, and IL-22 synergized with IL-17A and TNF-α. Furthermore, the IL-36s directly induced their own expression and the production of proinflammatory mediators (TNF-α, IL-6, IL-8) in KC. These functions were markedly enhanced with the addition of IL-17A or TNF-α to the cultures. Similarly, IL-36α and IL-36β augmented IL-17A-mediated induction of antibacterial peptides. Finally, we show that the increased gene expression of IL-36 correlated with Th17 cytokines in the lesions of psoriatic patients. Our results indicate that the IL-36 cytokines are not only regulated by Th17 cytokines, but that they themselves can regulate the expression and enhance the function of Th17 cytokines. We propose that a feedback loop between the IL-36 and Th17 cytokines is involved in driving cytokine expression in psoriatic tissues.

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…Moreover, these factors may contribute to the recruitment of immune cells, including neutrophils, which can further aggravate the inflammatory progression of psoriatic lesions through a crosstalk between keratinocytes and immune cells 21 . Besides IL-17 and cytokines such as IL-12 and IL-23 6 , IL-36 cytokines are important in psoriasis [24][25][26][27][28][29][30] . This is supported by our observations that IL-36 cytokines are induced in response to IL-17A in NHEKs, both in 3D models and in monolayer cultures, and that IL-36 inhibited keratinocyte differentiation in 3D models (Figs 1-3 and Supplementary Fig.…”

“…Members of the IL-36 family, which are IL-1 type cytokines, have also been implicated in psoriasis 22,23 . IL-36 cytokines are involved in the crosstalk between immune cells and keratinocytes and thus are potentially participating in controling the proinflammatory milieu in psoriatic skin [24][25][26][27][28][29][30] . Moreover, interaction of IL-17 and IL-36 has been postulated to promote inflammation 26,31 .…”

“…IL-36 cytokines are involved in the crosstalk between immune cells and keratinocytes and thus are potentially participating in controling the proinflammatory milieu in psoriatic skin [24][25][26][27][28][29][30] . Moreover, interaction of IL-17 and IL-36 has been postulated to promote inflammation 26,31 . Similar to IL-17, IL-36 also activates anti-microbial peptides 32,33 .…”

The Role of Cytokines of Interleukin 36 Family in Immunopathogenesis of Psoriasis

“…Было показано, что бло-кирование передачи сигнала на уровне IL-36R приводило к уменьшению в коже количества нейтрофильных гранулоцитов и макрофагов, значительному снижению экспрессии IL-17A γβ-Т-клетками и разрешению псориатических высыпаний [44]. Цитокины IL-17А, IFNγ, TNFα, IL-22 стимулируют продукцию кератиноцитами агонистов IL-36α, IL-36β, IL-36γ [6,14,23,33]. Представители семейства IL-36, в свою очередь, могут индуцировать секрецию кератиноцитами TNFα, IL-6 и антимикробных пептидов.…”

“…Кроме того, IL-36 совместно с IL-12 стимулирует про-дукцию CD4 + Т-клетками интерферона-γ (IFNγ), IL-4 и, в меньшей степени, IL-17 [49]. Аналогич-но представителям семейства IL-1, IL-36β по меха-низму аутокринно-паракринной регуляции может поддерживать собственную экспрессию, приводя к хронизации воспаления [6,23].…”