IL-23-Mediated Epidermal Hyperplasia Is Dependent on IL-6

Lindroos, Josefine; Svensson, Lars; Norsgaard, Hanne; Lovato, Paola; Möller, Kristian; Hagedorn, Peter; Olsen, Gunnar Marius; Labuda, Tord

doi:10.1038/jid.2010.432

Cited by 59 publications

(53 citation statements)

References 46 publications

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“…The cutaneous observations contradict prior findings in acute models of elicited psoriasiform skin inflammation in which IL-6, through promotion of IL-22 responses, may facilitate IL-23-mediated epidermal hyperproliferation (33). This alternative pathway has been reported to work even in the absence of IL-17A in the imiquimod psoriasiform model (34).…”

Section: Discussioncontrasting

confidence: 56%

Interleukin 6 regulates psoriasiform inflammation–associated thrombosis

et al. 2016

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Section: Discussioncontrasting

confidence: 56%

Interleukin 6 regulates psoriasiform inflammation–associated thrombosis

et al. 2016

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“…IL-23 may contribute to psoriasis by supporting the proliferation of Th17 cells, which produce proinflammatory cytokines, including IL-17 and IL-22 (25). IL-6 also plays a role in Th17 development and is upregulated in psoriatic skin and serum (26, 27). Upon imiquimod application, DCs produce IL-6 and IL-23 (Figure 6; (28)), causing Th17 and γδ T cells to produce proinflammatory cytokines such as IL-17 and IL-22.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of TYK2 and JAK1 Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis by Inhibiting IL-22 and the IL-23/IL-17 Axis

Works

Yin

et al. 2014

The Journal of Immunology

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Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making Janus kinase (JAK) inhibition an appealing strategy for the treatment of psoriasis. Here we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and Tyrosine Kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose-dependently (1 nM-10 μM) inhibited JAK1 and/or TYK2 dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild type mice with SAR-20347 significantly reduced IL-12 induced IFN-γ production and IL-22-dependent Serum Amyloid A (SAA) to similar extents, indicating that in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes, and proinflammatory cytokine levels compared to both TYK2 mutant mice and wild type controls. Taken together, these data indicate that targeting both JAK1 and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.

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“…IL-6 is involved in the differentiation of Th-17 cells and in the IL-23-induced skin inflammation. 74 IL-6 signaling through STAT3 is required for both IL-23 receptor expression and for IL-17A and IL-17F induction. 75 Unfortunately, there have been no studies in PsA; however, the IL-6 single nucleotide polymorphism rs1800795 was associated with a lower risk of PsV.…”

Section: Genetics Epigenetics and Pharmacogeneticsmentioning

confidence: 99%