EGFR transactivation is involved in TNF-α-induced expression of thymic stromal lymphopoietin in human keratinocyte cell line

Segawa, Ryosuke; Shigeeda, Kenichi; Hatayama, Takahiro; Dong, Jing; Mizuno, Natsumi; Moriya, Takuya; Hiratsuka, Masahiro; Hirasawa, Noriyasu

doi:10.1016/j.jdermsci.2017.12.008

Cited by 27 publications

(23 citation statements)

References 37 publications

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“…In one study, EGFR activation by EGF was found to protect against AD by decreasing IL-17A and IL-6 expression in an AD model 15 . Another study showed that transactivation of EGFR by TNF-α results in TSLP induction in keratinocytes 54 . However, amphiregulin, one of the EGFR ligands, suppressed dermatitis via EGFR 55 and epiregulin deficiency lead to chronic skin inflammation 56 .…”

Section: Discussionmentioning

confidence: 99%

Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice

Kim

Choi

Bak

et al. 2018

Sci Rep

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Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a complex, heterogeneous pathogenesis including skin barrier dysfunction, immunology, and pruritus. Although epidermal growth factor (EGF) is essential for epithelial homeostasis and wound healing, the effect of EGF on AD remains to be explored. To develop a new therapy for AD, the anti-AD potential of EGF was investigated by inducing AD-like skin lesions in NC/Nga mice using 2,4-dinitrochlorobenzene (DNCB). EGF was administrated to NC/Nga mice to evaluate its therapeutic effect on DNCB-induced AD. EGF treatment improved dermatitis score, ear thickness, epidermal hyperplasia, serum total immunoglobulin E level, and transepidermal water loss in NC/Nga mice with DNCB-induced AD. In addition, levels of skin barrier-related proteins such as filaggrin, involucrin, loricrin, occludin, and zonula occludens-1 (ZO-1) were increased by EGF treatment. These beneficial effects of EGF on AD may be mediated by EGF regulation of Th1/Th2-mediated cytokines, mast cell hyperplasia, and protease activated receptor-2 (PAR-2) and thymic stromal lymphopoietin (TSLP), which are triggers of AD. Taken together, our findings suggest that EGF may potentially protect against AD lesional skin via regulation of skin barrier function and immune response.

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Section: Discussionmentioning

confidence: 99%

Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice

Kim

Choi

Bak

et al. 2018

Sci Rep

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“…Activated dendritic cells express OX40L and promote differentiation of naive CD4 positive T cells into inflammatory Th2 cells, which aggravates allergies by releasing cytokines, such as IL-4, IL-5 and IL-13 [3]. TSLP production is induced by inflammatory cytokines, such as TNF-α [4], the activation of protease-activating receptors, toll-like receptors, and even by chemical compounds [5]. Both transcription factors NF-κB and AP-1 regulate the expression of human TSLP protein [6].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes

et al. 2019

Self Cite

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The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis.

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“…TSLP expression was verified to be regulated through EGFR transactivation in human and mouse keratinocytes. 44 We also found that ITGB4 deficiency in- Although our results provide that epithelial ITGB4 mediates pulmonary spontaneous inflammation and aggravated allergic immune response in early life, there are some limitations. The first one is that further lung insult exploration is needed to detect in ITGB4 deficiency mice, because it may also cause spontaneous inflammation.…”

Section: Discussionmentioning

confidence: 69%

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response

Tang

Lin

et al. 2020

J Cellular Molecular Medi

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Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early‐life lung immune responses are far from clear. Our previous study found that integrin β4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper‐responsiveness (AHR) with a house dust mite (HDM)‐induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4‐deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.

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EGFR transactivation is involved in TNF-α-induced expression of thymic stromal lymphopoietin in human keratinocyte cell line

Cited by 27 publications

References 37 publications

Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice

Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response

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