IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Wolk, Kerstin; Haugen, Harald S.; Xu, Wenfeng; Witte, Ellen; Waggie, Kim; Anderson, M; Baur, Elmar vom; Witte, Katrin; Warszawska, Katarzyna; Philipp, Sandra; Johnson‐Léger, Caroline; Volk, Hans‐Dieter; Sterry, Wolfram; Sabat, Robert

doi:10.1007/s00109-009-0457-0

Cited by 363 publications

(376 citation statements)

References 42 publications

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“…Overexpression of IL-22 results in psoriasis-like skin alterations in mice (36), and IL-22 deficiency protects mice from imiquimodinduced psoriasis-like skin inflammation (37). Here, we show that IL-22 is highly reduced in IκBζ-deficient mice receiving imiquimod, whereas IL-22 expression remains unaltered in IL-17A-deficient mice treated with imiquimod.…”

Section: Discussionmentioning

confidence: 57%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

128

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Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα-and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A-and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

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Section: Discussionmentioning

confidence: 57%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

128

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“…Underdeveloped EpiDerm-201 reconstituted human epidermis (RHE) tissues (MatTek, Ashland, MA) were cultured as described previously (24). In the first experimental setting, culture medium was supplemented or not (control) with recombinant human (rh)IL-22 (20 ng/ml), rhIL-20 (20 ng/ ml), rhIL-17A (10 ng/ml), rhIFN-g (10 ng/ml), or rhTNF-a (2 ng/ml), a cytokine mix containing rhIL-22 (1 ng/ml), rhIL-17A (1 ng/ml), rhIFN-g (0.1 ng/ml), rhIL-20 (5 ng/ml), and rhTNF-a (0.1 ng/ml), with the same mix with the exception of one of the T cell cytokines lacking at each time, or with the same mix containing varying concentrations of IL-22 (0.1, 1, and 10 ng/ml) at each time.…”

Section: Cell Culturementioning

confidence: 99%

Deficiency of IL-22 Contributes to a Chronic Inflammatory Disease: Pathogenetic Mechanisms in Acne Inversa

Wolk

Warszawska

Hoeflich

et al. 2011

The Journal of Immunology

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223

276

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Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1β. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10–inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI.

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“…IL-20 is thought to amplify the actions of IL-22 through a positive feedback loop [26,27]. IL-24 appears to be antiproliferative in the context of wound healing and also protects against bacterial infections [28].…”

Section: Discussionmentioning

confidence: 99%

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infectiondriven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations. @ERSpublications Neutrophil proteases alter lung antimicrobial defence and may predispose to infection-triggered COPD exacerbations http://ow.ly/MHqEt

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IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Cited by 363 publications

References 42 publications

IκBζ is a key driver in the development of psoriasis

IκBζ is a key driver in the development of psoriasis

Deficiency of IL-22 Contributes to a Chronic Inflammatory Disease: Pathogenetic Mechanisms in Acne Inversa

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

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