Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A

Rudloff, Ina; Bachmann, Michael; Pfeilschifter, Josef; Mühl, Heiko

doi:10.1074/jbc.m111.286492

Cited by 16 publications

(18 citation statements)

References 65 publications

(75 reference statements)

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“…Recently, we reported on robust IL-22 mRNA and promoter induction detected in Jurkat T cells stimulated by TPA/A23187 22 (see also Fig. 8a ).…”

Section: Resultsmentioning

confidence: 70%

“…Given the multilayered biological functions of IL-22, knowledge of molecular mechanisms driving its production is crucial. Previous reports indicate that transcription factors/nuclear receptors such as STAT3, retinoid orphan receptor-γt and aryl hydrocarbon receptor 21 as well as the cAMP response element-binding protein and nuclear factor of activated T cells (NF-AT) 22 are involved in initiation of IL-22 gene transcription. However, firm knowledge on post-transcriptional molecular mechanisms regulating IL-22 expression is lacking.…”

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confidence: 99%

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Tristetraprolin regulation of interleukin-22 production

Härdle

Bachmann

Bollmann

et al. 2015

Sci Rep

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Interleukin (IL)-22 is a STAT3-activating cytokine displaying characteristic AU-rich elements (ARE) in the 3′-untranslated region (3′-UTR) of its mRNA. This architecture suggests gene regulation by modulation of mRNA stability. Since related cytokines undergo post-transcriptional regulation by ARE-binding tristetraprolin (TTP), the role of this destabilizing protein in IL-22 production was investigated. Herein, we demonstrate that TTP-deficient mice display augmented serum IL-22. Likewise, IL-22 mRNA was enhanced in TTP-deficient splenocytes and isolated primary T cells. A pivotal role for TTP is underscored by an extended IL-22 mRNA half-life detectable in TTP-deficient T cells. Luciferase-reporter assays performed in human Jurkat T cells proved the destabilizing potential of the human IL-22-3′-UTR. Furthermore, overexpression of TTP in HEK293 cells substantially decreased luciferase activity directed by the IL-22-3′-UTR. Transcript destabilization by TTP was nullified upon cellular activation by TPA/A23187, an effect dependent on MEK1/2 activity. Accordingly, IL-22 mRNA half-life as determined in TPA/A23187-stimulated Jurkat T cells decreased under the influence of the MEK1/2 inhibitor U0126. Altogether, data indicate that TTP directly controls IL-22 production, a process counteracted by MEK1/2. The TTP-dependent regulatory pathway described herein likely contributes to the role of IL-22 in inflammation and cancer and may evolve as novel target for pharmacological IL-22 modulation.

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“…Recently, we reported on robust IL-22 mRNA and promoter induction detected in Jurkat T cells stimulated by TPA/A23187 22 (see also Fig. 8a ).…”

Section: Resultsmentioning

confidence: 70%

mentioning

confidence: 99%

Tristetraprolin regulation of interleukin-22 production

Härdle

Bachmann

Bollmann

et al. 2015

Sci Rep

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“…2B, PMA treatment resulted in a delayed increase in total IL1F7, which peaked at 24 h and was weaker than that induced by LPS (maximum 5-fold). To more-specifically investigate T cell-dependent IL1F7 regulation, we also stimulated PBMCs with anti-CD3, which activates T cells via T cell receptor ligation [30]. Similar to PMA, the increase in total IL1F7 induced by anti-CD3 was delayed; in fact, the maximum was reached as late as 48 h after anti-CD3 stimulation (Fig.…”

Section: Induction Of Il1f7 Expression In Pbmcs By Tlr Ligandsmentioning

confidence: 99%

Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells

Rudloff

Cho

Lao

et al. 2016

Journal of Leukocyte Biology

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The interleukin (IL)-1 family member IL-37 is one of few anti-inflammatory cytokines, and it is capable of countering a broad spectrum of proinflammatory assaults. Although it is known that leukocytes are a major source of IL-37, knowledge on IL-37 production and secretion in specific immune cell types remains limited. Thus, we investigated IL-37 mRNA expression as well as protein production and secretion in human PBMCs. In PBMCs stimulated with agonists of Toll-like receptors (TLRs) 1-6 and 9, (the IL-37-encoding gene) was induced up to 9-fold, peaked at 6-8 h and returned to steady-state at 72 h. LPS-induced expression comprised isoforms and but not and Flow cytometry revealed that among IL-37 PBMCs, monocytes predominated (81-91%), but T cells (6-8%) and myeloid dendritic cells (mDCs, 1-2%) also contributed to the IL-37 leukocyte pool. Monocytes and mDCs, but not T cells, were capable of secreting IL-37. Whereas monocytes and mDCs secreted IL-37 upon LPS stimulation, only mDCs also released IL-37 at steady-state. Among monocyte subsets, IL-37 was LPS inducible and secreted only in classical and, although less pronounced, in intermediate monocytes; secretion was observed as early as 3 h after stimulation. Overall, our data suggest that constitutive IL-37 secretion by mDCs may serve to maintain an anti-inflammatory milieu at steady state, whereas IL-37 is stored in monocytes to be available for rapid release upon inflammatory encounters, thus acting as a novel anti-inflammatory alarmin. These insights may prove important to advancing towards clinical use the protective functions of one of the most powerful anti-inflammatory mediators so far discovered.

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“…12 An in vitro T-cell model has recently demonstrated that in addition to the general immune-suppressive effects, CsA also directly inhibits IL-22 expression, possibly explaining its therapeutic benefit. 32 …”

Section: Introductionmentioning

confidence: 99%

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

Khattri

Shemer²,

Rozenblit

et al. 2014

Journal of Allergy and Clinical Immunology

157

194

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Background Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to Th2/Th22 cytokine activation. However, these models have not been tested by in-vivo suppression of T-cell cytokines. CsA is an immune-suppressant highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective To establish the ability of a systemic immune-suppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype, and to correlate changes with clinical improvement. Methods CsA effects on AD skin pathology were evaluated using geneexpression and immunohistochemistry studies in baseline, week 2 and 12 lesional and non-lesional biopsies from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in Scoring of AD/SCORAD. Clinical improvements were associated with significant gene expression changes in lesional but also non-lesional skin, particularly reductions of Th2-, Th22-, and some Th17-related molecules (i.e IL-13, IL-22, CCL17, S100As, elafin/PI3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune-antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

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Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A

Cited by 16 publications

References 65 publications

Tristetraprolin regulation of interleukin-22 production

Tristetraprolin regulation of interleukin-22 production

Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

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