The synergistic activities of the combination of tumour necrosis factor-α, interleukin-17A and interferon-γ in epidermal keratinocytes

Morizane, Shin; Nomura, Hayato; Tachibana, Koji; Nakagawa, Yuki; Iwatsuki, Keiji

doi:10.1111/bjd.16443

Cited by 8 publications

(9 citation statements)

References 9 publications

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“…We found that the inflammatory cytokine gene expression was significantly enhanced in response to TNF-α or IL-17A. Additionally, substantial synergistic effects of TNF-α and IL-17A were observed (Figure 5a), consistent with our previous study's findings [31]. Although palmitic acid alone did not significantly alter gene expression, it significantly amplified TNF-α-and IL-17A-mediated responses-especially the expression of CCL20, CXCL1, CXCL8, IL1B, and TNF (Figure 5a).…”

Section: Palmitic Acid and Leptin Regulate Inflammatory Responses Of ...supporting

confidence: 92%

“…All animal experiments were approved by the Institutional Safety Committee for Recombinant DNA Experiments (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) and the Institutional Animal Care and Use Committee of Kawasaki Medical School . All experimental procedures were conducted according to the institutional and NIH guidelines for the humane use of animals.…”

Section: Imq-induced Psoriasis Modelmentioning

confidence: 99%

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Obesity and Dyslipidemia Synergistically Exacerbate Psoriatic Skin Inflammation

Ikeda

Morizane

Akagi

et al. 2022

IJMS

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Patients with psoriasis are frequently complicated with metabolic syndrome; however, it is not fully understood how obesity and dyslipidemia contribute to the pathogenesis of psoriasis. To investigate the mechanisms by which obesity and dyslipidemia exacerbate psoriasis using murine models and neonatal human epidermal keratinocytes (NHEKs), we used wild-type and Apoe-deficient dyslipidemic mice, and administered a high-fat diet for 10 weeks to induce obesity. Imiquimod was applied to the ear for 5 days to induce psoriatic dermatitis. To examine the innate immune responses of NHEKs, we cultured and stimulated NHEKs using IL-17A, TNF-α, palmitic acid, and leptin. We found that obesity and dyslipidemia synergistically aggravated psoriatic dermatitis associated with increased gene expression of pro-inflammatory cytokines and chemokines. Treatment of NHEKs with palmitic acid and leptin amplified pro-inflammatory responses in combination with TNF-α and IL-17A. Additionally, pretreatment with palmitic acid and leptin enhanced IL-17A-mediated c-Jun N-terminal kinase phosphorylation. These results revealed that obesity and dyslipidemia synergistically exacerbate psoriatic skin inflammation, and that metabolic-disorder-associated inflammatory factors, palmitic acid, and leptin augment the activation of epidermal keratinocytes. Our results emphasize that management of concomitant metabolic disorders is essential for preventing disease exacerbation in patients with psoriasis.

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Section: Palmitic Acid and Leptin Regulate Inflammatory Responses Of ...supporting

confidence: 92%

Section: Imq-induced Psoriasis Modelmentioning

confidence: 99%

Obesity and Dyslipidemia Synergistically Exacerbate Psoriatic Skin Inflammation

Ikeda

Morizane

Akagi

et al. 2022

IJMS

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“…This indicated an impressive correlation between IL-17/TNF-α-induced genes and the psoriasis gene signature. We previously reported the more synergistic activities of the combined stimulation of TNF-α, IL-17A, and IFN-γ in epidermal keratinocytes [ 32 ]. For example, the triple stimulation synergistically induces IL-17C, IL-36γ, and the antimicrobial peptide human b-defensin-2 in epidermal keratinocytes [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported the more synergistic activities of the combined stimulation of TNF-α, IL-17A, and IFN-γ in epidermal keratinocytes [ 32 ]. For example, the triple stimulation synergistically induces IL-17C, IL-36γ, and the antimicrobial peptide human b-defensin-2 in epidermal keratinocytes [ 32 ]. Therefore, we predicted that normal human epidermal keratinocytes (NHEKs) stimulated with the triple cytokines would mimic the condition of psoriatic keratinocytes.…”

Section: Resultsmentioning

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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“…It has been evident that neutrophil‐derived pro‐inflammatory cytokines contribute to orchestrating the inflammatory response . Hence, we next assessed the mRNA expression of pro‐inflammatory cytokines (eg, IL‐1α, IL‐1β, IL‐6 and TNF‐α) and Th17‐related cytokines (eg, IL‐17, IL‐22 and IL‐23) in the skin lesions from IMQ‐treated WT and MBL −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Mannan‐binding lectin promotes keratinocyte to produce CXCL1 and enhances neutrophil infiltration at the early stages of psoriasis

Zeng

Chen

et al. 2019

Experimental Dermatology

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Psoriasis is a chronic, relapsing inflammatory skin disorder. Numerous experimental evidence and therapeutic evidence have shown that the innate immune response is critical for the pathogenesis and development of psoriasis. Mannan‐binding lectin (MBL), a prototypic pattern recognition molecule of the innate immune system, plays an essential role in the host defense against certain infections and also appears to be a major regulator of inflammation. In this study, we investigated the function of MBL on the course of experimental murine imiquimod (IMQ)‐induced psoriasis. Our data showed that MBL‐deficient (MBL−/−) mice exhibited attenuated skin damage characterized by greatly decreased erythema compared with wild‐type control mice during the early stages of IMQ‐induced psoriasis‐like skin inflammation. The reduced skin inflammation in MBL−/− mice was associated with the decreased infiltration of neutrophils. Furthermore, we have determined that MBL deficiency limited the chemokine CXCL1 production from skin keratinocytes upon IMQ stimulation, which might be responsible for the impaired skin recruitment of neutrophils. Additionally, we have provided the data that MBL protein promotes the IMQ‐induced expression of CXCL1 and activation of MAPK/NF‐κB signalling pathway in human keratinocyte HaCaT cells in vitro. In summary, our study revealed an unexpected role of MBL on keratinocyte function in skin, thus offering a new insight into the pathogenic mechanisms of psoriasis.

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The synergistic activities of the combination of tumour necrosis factor-α, interleukin-17A and interferon-γ in epidermal keratinocytes

Cited by 8 publications

References 9 publications

Obesity and Dyslipidemia Synergistically Exacerbate Psoriatic Skin Inflammation

Obesity and Dyslipidemia Synergistically Exacerbate Psoriatic Skin Inflammation

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

Mannan‐binding lectin promotes keratinocyte to produce CXCL1 and enhances neutrophil infiltration at the early stages of psoriasis

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