Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis

Zheng, Yan; Danilenko, Dimitry M.; Valdez, Patricia; Kasman, Ian; Eastham-Anderson, Jeffrey; Wu, Jianfeng; Ouyang, Wenjun

doi:10.1038/nature05505

Cited by 1,690 publications

(1,685 citation statements)

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“…IL-23 acts on memory-type cells [2] and induces the production of IL-17 [3] and IL-22 [4]. Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, IL-22, IL-6 and TNF-a [6].…”

Section: Introductionmentioning

confidence: 99%

“…The in vitro differentiation of Th17 cells produces a population of cells with a single expression of IL-17 and IL-22 and the coexpression of IL-17 and IL-22 [16]. Although both IL-6 and TGF-b are necessary for Th17 cell differentiation, IL-6 or IL-23 induces IL-22 production, whereas TGF-b inhibits IL-22 production [4]. Recent studies have revealed that ligation of the aryl hydrocarbon receptor (AHR) drives Th17 differentiation and IL-22 production [20].…”

Section: Introductionmentioning

confidence: 99%

“…IL-22 has both proinflammatory/pathological and protective properties, depending on the inflammatory context [21]. The proinflammatory/pathological nature is apparent in mouse models with diseases such as psoriasis [4] and rheumatoid arthritis [22], and T. gondii infection [11]. In contrast, IL-22 plays protective roles and has tissue-protective and antimicrobial properties in several mouse models with diseases such as inflammatory bowel disease (IBD) [23], hepatitis [24] and infection with invading pathogenic bacteria [10,25,26].…”

Section: Introductionmentioning

confidence: 99%

“…Mice that are deficient in RBP-J, a key mediator of Notch signaling, are highly susceptible to the detrimental immunopathology associated with Con A-induced hepatitis with little IL-22 production [29]. IL-6 has the ability to induce IL-22 production [4], and IL-6-deficient mice were shown to be highly susceptible to liver damage [30]. However, IL-6-deficient mice were reported to have no impairment in IL-22 expression during Con A-induced hepatitis [24].…”

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Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Morishima

Mizoguchi

et al. 2011

Eur J Immunol

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IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting . Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19-and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-c and TNF-a. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.Key words: Hepatitis . IL-17 . IL-22 . IL-23Supporting Information available online Introduction IL-23 is a heterodimeric cytokine which belongs to the IL-6/IL-12 family and plays a key role in autoimmune and inflammatory disorders [1]. IL-23 acts on memory-type cells [2] and induces the production of . Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, . p19-deficient mice are highly resistant to the development of experimental allergic encephalomyelitis (EAE) [7], and it has been shown that the IL-23-dependent production of IL-17, but not , is important for the pathogenesis of autoimmune 2828diseases such as EAE [9]. Recent studies have also revealed that the IL-23-dependent production of IL-22, but not IL-17, plays a critical role in protection against subsequent infection. In infection with an attenuated strain of Salmonella enterica serovar Enteritidis, p19-deficient mice showed reduced survival and exacerbated liver necrosis only in the absence of IL-12 in an IL-17-independent manner [10]. In peroral infection with Toxoplasma gondii, which leads to the development of small intestine inflammation, the IL-23-dependent upregulation of IL-22 is essential for the development of ileitis; on the other hand, IL-17 is downregulated and dispensable [11].IL-22 is a member of the IL-10 cytokine family and plays important roles in inflammation, immune surveillance and tissue homeostasis [12][13][14][15] [10,25,26].Recently, we demonstrated that Notch, which is an evolutionally conserved molecule that controls cell fate decision in a variety of cells [27,28], drives IL-22 secretion by stimu...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Morishima

Mizoguchi

et al. 2011

Eur J Immunol

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“…In cutaneous infection or inflammation, dermal or epidermal APC such as DC, Langerhans cells, and macrophages are increased and activated, and these abundantly produce IL-12, IL-23, and IL-27 [11][12][13]. In particular, IL-12 and IL-23 production is highly enhanced in psoriatic skin lesions [11].…”

Section: Introductionmentioning

confidence: 99%

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

Kanda¹,

Watanabe²

2008

Eur J Immunol

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IL-12, IL-23, and IL-27, which are produced by APC, modulate innate and adaptive immunities. Human b-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense and inflammation. We examined the in vitro effects of IL-12, IL-23, and IL-27 on hBD-2 production in human keratinocytes. IL-12, IL-23, and IL-27 enhanced IL-1b-induced hBD-2 secretion and mRNA expression in keratinocytes. The stimulatory effects of IL-12, IL-23, and IL-27 were suppressed by antisense oligonucleotides against NF-jB p50 and p65. In addition, the effects of IL-12 and IL-27 were suppressed by antisense STAT3 and STAT1, respectively. All the three IL enhanced the basal and IL-1b-induced transcriptional activities of NF-jB, while IL-12 and IL-27 enhanced STAT3 and STAT1 activities, respectively. Further, IL-12, IL-23, and IL-27 promoted basal and IL-1b-induced phosphorylation of IjBa. IL-12 and IL-23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL-12, IL-23, and IL-27 tyrosine phosphorylated JAK2 and tyrosine kinase-2; and IL-27 tyrosine phosphorylated JAK1. These results suggest that IL-12, IL-23, and IL-27 may enhance IL-1b-induced hBD-2 production in keratinocytes by activating NF-jB. STAT3 and STAT1 are involved in the effects of IL-12 and IL-27, respectively. Thus, IL-12, IL-23, and IL-27 may promote cutaneous antimicrobial defense and inflammation via hBD-2.

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CCL20andIL22Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis

et al. 2015

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IMPORTANCE Methotrexate is a first-line systemic agent for treating of psoriasis, although its onset of effects is slower and overall it is less effective than tumor necrosis factor blockers. OBJECTIVE To differentiate the response of psoriatic disease to adalimumab and methotrexate sodium. DESIGN, SETTING, AND PARTICIPANTS Single-center, randomized, assessor-blind, 2-arm clinical trial of 30 patients from the outpatient dermatology center of Tufts Medical Center, enrolled from August 18, 2009, to October 11, 2011. Patients aged 18 to 85 years with chronic plaque-type psoriasis, a minimum Physician Global Assessment score of 3 (higher scores indicate more severe disease), and a psoriatic plaque of at least 2 cm were randomized in a 1:1 fashion to receive subcutaneous adalimumab or oral methotrexate. Skin biopsy specimens obtained at baseline and weeks 1, 2, 4, and 16 were given a histologic grade by blinded assessors to evaluate treatment response. Analyses were conducted from April 16, 2013, to January 5, 2015. INTERVENTIONS A 16-week course of subcutaneous adalimumab (40 mg every 2 weeks after a loading dose) or low-dosage oral methotrexate sodium (7.5–25 mg/wk). MAIN OUTCOMES AND MEASURES Changes in genomic, immunohistochemical, and messenger RNA (mRNA) profiles. RESULTS Methotrexate responders experienced significant downregulation of helper T-cell– related (TH1, TH17, and TH22) mRNA expression compared with methotrexate nonresponders. Comparisons among adalimumab-treated patients were limited by the number of nonresponders (n = 1). Between adalimumab and methotrexate responders, we found no significant differences in gene expression at any study point or in the expression of T-cell–related mRNA at week 16. Adalimumab responders demonstrated early downregulation of chemokine (C-C motif) ligand 20 (CCL20) mRNA (mean [SE] at week 2, −1.83 [0.52], P < .001; week 16, −3.55 [0.54], P < .001) compared with late downregulation for methotrexate responders (week 2, 0.02 [0.51], P = .96; week 16, −2.96 [0.51], P < .001). Similar differences were observed with interleukin 22 (IL22) mRNA showing early downregulation for adalimumab responders (week 2, −3.17 [1.00], P < .001; week 16, −3.58 [1.00], P < .001) compared with late downregulation for methotrexate responders (week 2, −0.44 [0.68], P = .64; week 16, −5.14 [0.68], P < .001). Analysis of variance findings for key mRNA and immunohistochemical marker expression over the study course were significant only for CCL20 (P = .03) and IL22 (P = .006) mRNA comparing adalimumab and methotrexate responders. CONCLUSIONS AND RELEVANCE Methotrexate is an immunomodulator with effects on helper T-cell signaling in psoriasis. Similar genomic and immunohistochemical response signatures and levels of mRNA downregulation at study completion among adalimumab and methotrexate responders suggest a disease-driven instead of therapeutic-driven pathway regulation. Adalimumab and methotrexate responses are differentiated by patterns of normalization of CCL20 and IL22 mRNA expres...

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Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis

Cited by 1,690 publications

References 30 publications

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

CCL20andIL22Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis

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