Disrupting the DNA Binding of EGR-1 with a Small-Molecule Inhibitor Ameliorates 2,4-Dinitrochlorobenzene-Induced Skin Inflammation

Yeo, Hyunjin; Ahn, Sung Shin; Lee, Jeong Yeon; Jung, Euitaek; Jeong, Munki; Kang, Gi Sue; Ahn, Seunghyun; Lee, Youngshim; Koh, Dongsoo; Lim, Yoongho; Shin, Soon Young

doi:10.1016/j.jid.2020.12.029

Cited by 14 publications

(13 citation statements)

References 15 publications

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“…To investigate whether chrysin modulates TSLP expression, we used TNFα as a positive signal to induce TSLP expression. As reported in a previous study [42], the TSLP mRNA levels were enhanced upon TNFα stimulation, as shown using reverse transcription (RT)-PCR (Figure 1B). However, chrysin pretreatment abrogated the ability of TNFα to induce TSLP mRNA expression.…”

Section: Chrysin Inhibits Tnfα-induced Tslp Expression In Hacat Keratinocytessupporting

confidence: 86%

“…TNFα is a pro-inflammatory cytokine that promotes inflammation by inducing the production of various other inflammatory cytokines and chemokines [ 40 ]. TNFα production was enhanced in a mouse model of 2.4-dinitrobenzene (DNCB)-induced contact allergy [ 41 ], and TNFα induced TSLP expression in skin keratinocytes [ 42 ]. To investigate whether chrysin modulates TSLP expression, we used TNFα as a positive signal to induce TSLP expression.…”

Section: Resultsmentioning

confidence: 99%

“…EGR1 regulates the expression of genes encoding inflammation-related proteins, such as IL-33-induced TSLP [ 45 ], IL-17-induced psoriasin [ 61 ], and IL-13-induced kallikrein-related peptidase 7 (KLK7) in keratinocytes [ 62 ]. Recently, we demonstrated that immune cell infiltration in AD-like skin lesions was substantially attenuated in Egr1 -knockout mice, and the TNFα-induced expression of cytokines, including TSLP, IL-1β, IL-6, CXCL1, CCL2, and CCL5, was inhibited in response to EGR1 knockdown [ 42 ]. Furthermore, the AB1711 compound, a small-molecule inhibitor targeting the EGR1 zinc-finger DNA-binding domains, was shown to abrogate the expression of EGR1-regulated inflammatory cytokines in keratinocytes and improve both skin inflammation and itching in DNCB-challenged NC/Nga mice [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we demonstrated that immune cell infiltration in AD-like skin lesions was substantially attenuated in Egr1 -knockout mice, and the TNFα-induced expression of cytokines, including TSLP, IL-1β, IL-6, CXCL1, CCL2, and CCL5, was inhibited in response to EGR1 knockdown [ 42 ]. Furthermore, the AB1711 compound, a small-molecule inhibitor targeting the EGR1 zinc-finger DNA-binding domains, was shown to abrogate the expression of EGR1-regulated inflammatory cytokines in keratinocytes and improve both skin inflammation and itching in DNCB-challenged NC/Nga mice [ 42 ]. These findings suggest that the inhibition of EGR1 transcriptional activity is a promising therapeutic strategy for improving therapeutic efficacy in chronic skin inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Yeo

Lee

Ahn

et al. 2021

IJMS

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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.

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Section: Chrysin Inhibits Tnfα-induced Tslp Expression In Hacat Keratinocytessupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Yeo

Lee

Ahn

et al. 2021

IJMS

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“…It is involved in the regulation of immune responses [ 24 ]. In the skin, EGR1 mediates TNFα-induced inflammatory cytokines, including TSLP, and Egr1 deficiency ameliorated AD-like skin inflammation in a mouse model [ 25 ]. These findings suggest that EGR1 is crucial for cutaneous inflammatory response through TSLP expression in inflammatory skin conditions.…”

Section: Resultsmentioning

confidence: 99%

β-Caryophyllene Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis through the Downregulation of Mitogen-Activated Protein Kinase/EGR1/TSLP Signaling Axis

Ahn

Yeo

Jung

et al. 2022

IJMS

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Atopic dermatitis (AD) is one of the most common inflammatory skin diseases accompanied by severe itching. β-caryophyllene (BCP), which displays anti-inflammatory activity, is a natural agonist of cannabinoid receptor 2. However, the therapeutic effects of BCP on atopic dermatitis (AD) remain poorly understood. The current study aimed to evaluate the topical therapeutic efficacy of BCP in an AD-like mouse model. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that drives AD pathogenesis. This study also investigated the effect of BCP on the interleukin 4 (IL-4)-induced expression of TSLP in HaCaT keratinocytes. We found that the topical application of BCP alleviated AD-like skin inflammation and inhibited the infiltration of proinflammatory cells into skin lesions. Moreover, the topical application of BCP reduced EGR1 (Early Growth Response 1) and TSLP expression in AD-like skin lesions. We also found that BCP inhibited IL-4-induced TSLP expression by downregulating mitogen-activated protein kinase (MAPK)-mediated EGR1 expression in HaCaT keratinocytes. These findings demonstrate that BCP ameliorates DNCB-induced AD-like skin lesions through the downregulation of the MAPK/EGR1/TSLP signaling axis. BCP may be applicable for developing topical therapeutic agents for chronic skin inflammatory diseases, such as AD.

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Early Growth Response Gene-1 Deficiency Interrupts TGFβ1 Signaling Activation and Aggravates Neurodegeneration in Experimental Autoimmune Encephalomyelitis Mice

Lan,

Han,

Huang

et al. 2023

Neurosci. Bull.

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Disrupting the DNA Binding of EGR-1 with a Small-Molecule Inhibitor Ameliorates 2,4-Dinitrochlorobenzene-Induced Skin Inflammation

Cited by 14 publications

References 15 publications

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

β-Caryophyllene Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis through the Downregulation of Mitogen-Activated Protein Kinase/EGR1/TSLP Signaling Axis

Early Growth Response Gene-1 Deficiency Interrupts TGFβ1 Signaling Activation and Aggravates Neurodegeneration in Experimental Autoimmune Encephalomyelitis Mice

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