Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes

Ehst, Benjamin D.; Wang, Zhiping; Leitenberger, Justin J.; McClanahan, Danielle; Torre, R. De La; Sawka, Erika; Ortega‐Loayza, Alex G.; Strunck, Jennifer L.; Greiling, Teri M.; Simpson, Eric L.; Liu, Yuangang

doi:10.1016/j.cyto.2020.155357

Cited by 21 publications

(14 citation statements)

References 41 publications

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“…On the other hand, some research groups have reported the production of IL-23 by human keratinocytes, in contrast to our results. Ehst et al reported that IL-23 protein was enhanced upon stimulation of human keratinocytes by TNF-α plus IL-17A [ 41 ]. Li et al showed that keratinocytes could produce IL-23 at levels sufficient to cause differentiation of IL-17A-producing T cells and skin inflammation in a mouse model [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Multifaceted Analysis of IL-23A- and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

Tachibana

Tang

Urakami

et al. 2021

IJMS

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Interleukin (IL) 23 (p19/p40) plays a critical role in the pathogenesis of psoriasis and is upregulated in psoriasis skin lesions. In clinical practice, anti-IL-23Ap19 antibodies are highly effective against psoriasis. IL-39 (p19/ Epstein-Barr virus-induced (EBI) 3), a newly discovered cytokine in 2015, shares the p19 subunit with IL-23. Anti-IL-23Ap19 antibodies may bind to IL-39; also, the cytokine may contribute to the pathogenesis of psoriasis. To investigate IL23Ap19- and/or EBI3-including cytokines in psoriatic keratinocytes, we analyzed IL-23Ap19 and EBI3 expressions in psoriasis skin lesions, using immunohistochemistry and normal human epidermal keratinocytes (NHEKs) stimulated with inflammatory cytokines, using quantitative real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and liquid chromatography-electrospray tandem mass spectrometry (LC-Ms/Ms). Immunohistochemical analysis showed that IL-23Ap19 and EBI3 expressions were upregulated in the psoriasis skin lesions. In vitro, these expressions were synergistically induced by the triple combination of tumor necrosis factor (TNF)-α, IL-17A, and interferon (IFN)-γ, and suppressed by dexamethasone, vitamin D3, and acitretin. In ELISA and LC-Ms/Ms analyses, keratinocyte-derived IL-23Ap19 and EBI3, but not heterodimeric forms, were detected with humanized anti-IL-23Ap19 monoclonal antibodies, tildrakizumab, and anti-EBI3 antibodies, respectively. Psoriatic keratinocytes may express IL-23Ap19 and EBI3 proteins in a monomer or homopolymer, such as homodimer or homotrimer.

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Section: Discussionmentioning

confidence: 99%

Multifaceted Analysis of IL-23A- and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

Tachibana

Tang

Urakami

et al. 2021

IJMS

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“…A recent report has shown that EGFR activation increases IL‐17A/TNF‐α‐induced IL‐23A expression in keratinocytes [20]. This study investigated whether EGFR ligands regulate the expression of various psoriasis signature genes, including IL‐23A in NHEKs, and their possible mechanism of action.…”

Section: Resultsmentioning

confidence: 99%

EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3

et al. 2022

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Various epidermal growth factor receptor (EGFR) ligands are highly expressed in the epidermis of psoriasis lesions, and abnormal EGFR activation appears to be involved in the pathogenesis of psoriasis. However, how EGFR signaling contributes to the development of psoriasis is unclear. Interleukin (IL)‐17A, a critical effector of the IL‐23/IL‐17A pathway, increases the expression of psoriasis signature genes in keratinocytes and plays an essential role in the pathogenesis of psoriasis by inducing IκBζ, a critical transcriptional regulator in psoriasis. In this study, we stimulated primary human keratinocytes with IL‐17A and various EGFR ligands to investigate whether EGFR ligands regulate the expression of psoriasis signature genes. In cultured normal human keratinocytes and a living skin equivalent, EGFR ligands did not induce psoriasis‐related gene expression, but significantly enhanced the IL‐17A‐mediated induction of various psoriasis signature genes, including antimicrobial peptides, cytokines, and chemokines. This was dependent on an EGFR activation‐mediated synergistic increase in IL‐17A‐induced IκBζ expression and was partially mediated by the EGFR‐dependent upregulation of Bcl3. Therefore, EGFR ligands can act as synergistic agents of IL‐17A signaling by stimulating the epidermal production of psoriasis signature genes in psoriasis lesions. This study reveals a potential mechanism by which EGFR signaling contributes to the pathogenesis of psoriasis.

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“…Growth factors and their receptors such as VEGFA, EGF, and EGFR were also inextricably linked with psoriasis [41][42][43][44]. e above point of view had long become a consensus in dermatology.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Huoluo Xiaoling Dan in the Treatment of Psoriasis Based on Network Pharmacology and Molecular Docking

Gong

Guo

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To explore the mechanism of the action of Huoluo Xiaoling Dan (HLXLD) in the treatment of psoriasis based on network pharmacology and molecular docking. Methods. The main active components and targets of HLXLD were collected from CMSP, and the targets related to psoriasis were collected from GeneCards, OMIM, TTD, DisGeNET, and DrugBank. Drug disease target genes were obtained by Venny tools, drug-component-target networks were constructed and analyzed, and pathway enrichment analysis was performed. AutoDockTools is used to connect the core components and the target, and PyMOL software is used to visualize the results. Results. 126 active components (such as quercetin, luteolin, tanshinone IIA, dihydrotanshinlactone, and beta-sitosterol) and 238 targets of HLXLD were screened out. 1,293 targets of psoriasis were obtained, and 123 drug-disease targets were identified. Key targets included AKT1, TNF, IL6, TP53, VEGFA, JUN, CASP3, IL1B, STAT3, PTGS2, HIF1A, EGF, MYC, EGFR, MMP9, and PPARG. Enrichment analysis showed that 735 GO analysis and 85 KEGG pathways were mainly involved in biological processes such as response to the drug, inflammatory response, gene expression, and cell proliferation and apoptosis, as well as signal pathways such as cancer, TNF, HIF-1, and T cell receptor. Molecular docking showed that there was strong binding activity between the active ingredient and the target protein. Conclusions. HLXLD could treat psoriasis through multicomponents, multitargets, and multipathways, which provides a new theoretical basis for further basic research and clinical application.

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Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes

Cited by 21 publications

References 41 publications

Multifaceted Analysis of IL-23A- and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

Multifaceted Analysis of IL-23A- and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3

Mechanism of Huoluo Xiaoling Dan in the Treatment of Psoriasis Based on Network Pharmacology and Molecular Docking

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