Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation

Nadeem, Ahmed; Al-Harbi, Naif O.; Al-Harbi, M. M.; El-Sherbeeny, Ahmed M.; Ahmad, Sheikh F.; Siddiqui, Nahid; Ansari, Mushtaq A.; Zoheir, Khairy M.A.; Attia, Sabry M.; Alhosaini, Khaled; Al-Sharary, Shakir D.

doi:10.1016/j.phrs.2015.06.001

Cited by 107 publications

(66 citation statements)

References 39 publications

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“…Significantly, we have also previously reported that either BRD2 deletion or BET protein inhibition reduces IL-6 and TNF-α production in lipopolysaccharide-challenged macrophages (26). Other studies have reported that BET targeting leads to diminished production of pro-inflammatory cytokines in models of various pathologies (25,50). Therefore, BET proteins constitute a promising therapeutic target within the breast tumor microenvironment to resolve inflammation and disrupt de facto its effects on tumor progression and dissemination.…”

Section: Discussionmentioning

confidence: 94%

BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

et al. 2016

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The Bromodomain and ExtraTerminal (BET) proteins are epigenetic ‘readers’ of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression, and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion. BRD4, but not BRD2 or BRD3, regulated Jagged1 expression and Notch1 signaling. BRD4-selective knockdown suppressed Notch1 activity and impeded breast cancer migration and invasion. BRD4 was required for interleukin-6-stimulated, Notch1-induced migration and invasion, coupling microenvironment inflammation with cancer propagation. Moreover, in patients, BRD4 and Jagged1 expression positively correlated with the presence of distant metastases. These results identify a BRD4/Jagged1/Notch1 signaling pathway that is critical for dissemination of triple-negative breast cancer.

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Section: Discussionmentioning

confidence: 94%

BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

et al. 2016

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“…The mice in IMQ, TC and TC + ZnPP groups received a daily topical dose of 62.5 mg and 5mg of commercial IMQ cream (Aldara 5%; MEDA Pharma, Germany) on the shaved back and right ear respectively for 7 consecutive days, as described previously [18][19][20]. The mice wore plastic collars to avoid licking IMQ on the skin.…”

Section: Animal Treatmentmentioning

confidence: 99%

Terminalia Chebulanin Attenuates Psoriatic Skin Lesion via Regulation of Heme Oxygenase-1

Li²,

Dong³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Psoriasis is one of the most common inflammatory skin disorders, affecting 3% of the general population. Terminalia chebulanin (TC) is a polyphenolic compound that possesses antioxidant and anti-inflammatory activities. The current study was designed to investigate the effect of TC on psoriatic lesions. Methods: We examined the protective effect of TC against psoriatic lesions in mice and keratinocyte proliferation in HaCaT cells. Results: We found that TC exhibited potent anti-psoriatic activities, as evidenced by improvement of erythema and scaling scores, decrease of epidermal, ear and skinfold thickening, decrease of tumor necrosis factor α (TNFα), interleukin (IL)-17A, IL-23 and matrix metalloproteinase (MMP)-9 expression, and decrease of TBARS content and increase of GSH content in IMQ-treated mice, and decrease of keratinocyte proliferation, TNFα, IL-17A and IL-23 expression, and ROS level in M5-treated cells. All those effects induced by TC were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase (HO)-1, indicating that HO-1 was responsible the anti-psoriatic effect of TC. Moreover, TC inhibited the upregulation of p65 NF-κB under in vitro psoriatic condition. ZnPP suppressed TC-induced inhibition of p65 NF-κB expression. Overexpression of p65 NF-κB significantly suppressed TC-induced decrease of TNFα, IL-17A and IL-23 expression and keratinocyte proliferation, indicating that HO-1-mediated downregulation of NF-κB was involved in the anti-psoriatic effect of TC. Conclusions: The data demonstrate that TC may serve as a potential therapeutic option for psoriatic patients.

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“…Although not yet directly demonstrated in humans, T2D is likely accompanied by an inflammatory microenvironment in breast adipose tissue that could exacerbate breast cancer risk. Common inflammatory mediators implicated in T2D and breast cancer, which are also regulated by BET proteins, include IL-6, TNF-α, IL-1β, and IL-17A [122, 132, 133]. The association of Th17 cytokines with both T2D and breast cancer, coupled with BET proteins’ unique ability to regulate Th17 inflammation via multiple mechanisms, makes BET bromodomain inhibitors potentially strong candidates for the treatment of Th17 inflammation [18, 133].…”

Section: Discussionmentioning

confidence: 99%

“…JQ1 inhibits retinoic acid receptor-related orphan receptor C (RORC— the Th17 master regulatory transcription factor) gene and protein expression in psoriatic mice [133]. By diminishing expression of RORC, BET inhibition reduces differentiation of Th17 cells as well as production of IL-17 and IL-22, which play a central role in Th17 inflammation as discussed above.…”

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

“…Complementing in vitro studies, preclinical and animal models indicate that BET inhibitors are effective for the treatment of inflammatory diseases in vivo (Table 1). Administration of JQ1 alleviates inflammation in mouse models of psoriasis, rheumatoid, and osteoarthritis (RA and OA), and multiple sclerosis (MS) [122, 127, 133, 135]. The ability of BET inhibition to treat these inflammatory diseases effectively in mice implies that BET inhibitors may be useful for the treatment of chronic inflammation associated with obesity, T2D, and breast cancers through epigenetic disruption of cytokine networks.…”

Section: Bet Inhibitors and Clinical Applications For Inflammationmentioning

confidence: 99%

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BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Nicholas

Andrieu

Strissel

et al. 2016

Cell. Mol. Life Sci.

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Chronic inflammation drives pathologies associated with type 2 diabetes (T2D) and breast cancer. Obesity-driven inflammation may explain increased risk and mortality of breast cancer with T2D reported in the epidemiology literature. Therapeutic approaches to target inflammation in both T2D and cancer have so far fallen short of the expected improvements in disease pathogenesis or outcomes. The targeting of epigenetic regulators of cytokine transcription and cytokine signaling offers one promising, untapped approach to treating diseases driven by inflammation. Recent work has deeply implicated the Bromodomain and Extra-Terminal domain (BET) proteins, which are acetylated histone “readers”, in epigenetic regulation of inflammation. This review focuses on inflammation associated with T2D and breast cancer, and the possibility of targeting BET proteins as an approach to regulating inflammation in the clinic. Understanding inflammation in the context of BET protein regulation may provide a basis for designing promising therapeutics for T2D and breast cancer.

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Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation

Cited by 107 publications

References 39 publications

BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

Terminalia Chebulanin Attenuates Psoriatic Skin Lesion via Regulation of Heme Oxygenase-1

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

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