IL-1F5, -F6, -F8, and -F9: A Novel IL-1 Family Signaling System That Is Active in Psoriasis and Promotes Keratinocyte Antimicrobial Peptide Expression

Abstract

IL-1F6, IL-1F8 and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control (NN), uninvolved psoriasis (PN) and psoriasis plaque (PP) skin using QRT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2-3 orders of magnitude in PP versus PN skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8 and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8 and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1α and TNF-α induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of anti-microbial peptides and matrix metalloproteins by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of HBD2, HBD3 and CAMP and protein secretion of HBD2 and HBD3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies.

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

“…IL-36 cytokines are overexpressed in affected skin of patients with inflammatory skin diseases, including atopic dermatitis and psoriasis (25)(26)(27)(28). The functional importance of this upregulation is supported by several recent findings: IL-36g mediates the alarmin function of the antimicrobial peptide LL37, and it functions as an alarmin that signals pathogen infections (20,29); injection of IL-36a promotes myeloid cell infiltration and their activation in the skin (30); tg mice overexpressing IL-36a in keratinocytes develop a psoriasis-like phenotype (31); the psoriasiform dermatitis that develops in mice after treatment with imiquimod depends on an IL-36-mediated cross-talk between dendritic cells and keratinocytes (32); and IL-36RA deficiency causes generalized pustular psoriasis in humans (33).…”

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

“…In addition, IL-4 inhibits IL-1b-and IL-17A-induced antimicrobial peptide expression in normal skin and hBD2 protein in psoriatic skin ex vivo, a hallmark of psoriatic lesional epidermal skin. Psoriatic EC produce increased levels of several members of the IL-1 family of cytokines including IL-1b (36), which is capable of inducing the regenerative epidermal phenotype in normal human skin (9,(37)(38)(39), and upregulates IL-6, IL-8, TNF-a, and hBD2 expression (36,37). More importantly, IL-1b together with IL-23 is crucial in inducing Th17 and Th22 differentiation and IL-17 and IL-22 production (6, 40).…”

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

“…Проведенные исследования показали, что в по-раженной коже больных псориазом наблюдается повышенная экспрессия IL-36α и IL-36γ [5,23]. IL-36γ можно рассматривать в качестве специ-фического маркера псориаза, который не встре-чается при других воспалительных заболеваниях кожи (нейродермит, красный плоский лишай, экзема).…”

“…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].…”