Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Jung, Sang Hoon; Sun, Xiaoyan; Ryu, Wang Shick; Yang, Beomjoo

doi:10.1111/bjd.12069

Cited by 12 publications

(16 citation statements)

References 50 publications

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“…The ability of bosutinib and dasatinib to manipulate macrophage fate towards an anti-inflammatory phenotype by inhibiting the SIKs has several implications for the treatment of chronic inflammatory and autoimmune diseases in the clinic. Although the present report provides early evidence of potential anti-inflammatory actions of bosutinib, dasatinib has been shown by others to prevent the development of the cardinal features of disease in experimental models of inflammatory arthritis and allergic contact dermatitis [ 33 , 34 ]. Dasatinib has also been found to reduce neuro-inflammation in mouse models of Alzheimer's disease [ 35 ].…”

Section: Discussionmentioning

confidence: 94%

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

Ozanne

Prescott

Clark

2015

Biochemical Journal

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Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of ‘regulatory’-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of ‘regulatory’-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of ‘regulatory’-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.

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Section: Discussionmentioning

confidence: 94%

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

Ozanne

Prescott

Clark

2015

Biochemical Journal

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“…DNFB-induced ACD caused severe inflammation in ear tissues showing a typical dermatopathological appearance of ACD, namely, hyperkeratosis, and spongiosis together with marked edema in the epidermis and dermis associated with a massive infiltration of inflammatory cells [17]. For histopathological analysis, we excised the ear on day 11 after challenging with DNFB and stained it with hematoxylin-eosin.…”

Section: Resultsmentioning

confidence: 99%

Extract ofRhus vernicifluaBark Suppresses 2,4-Dinitrofluorobenzene-Induced Allergic Contact Dermatitis

Park

Lee²,

Park

2013

Evidence-Based Complementary and Alternative Medicine

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Rhus verniciflua Stokes (RV) has traditionally been used as a food supplement and a traditional herbal medicine for centuries in Korea. Recent studies suggest that RV has potent antioxidative, antitumor, and anti-inflammatory properties. In this study, the anti-inflammatory effects of RV from mice sensitized with 2,4-dinitrofluorobenzene (DNFB) and activated macrophages were investigated. The results showed that RV reduced ear swelling and hyperplasia of ear tissue as well as an increase in vascular permeability, which are characteristics of allergic contact dermatitis (ACD) with evident histomorphological changes in epidermis and dermis. Decreased numbers of infiltrated mast cells were seen in RV extract treated group, using toluidine blue staining. RV extract significantly regulates the expression of inducible nitric oxide synthase (iNOS) at the translational level in activated macrophages. Furthermore, RV extract and its active compound, fisetin, attenuated the level of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) mRNA in LPS-stimulated macrophages. Anti-ACD effect of RV extract may be due to the suppression of iNOS and proinflammatory cytokines which might be mediated via the NFκB signaling pathways. Collectively, RV extract has potential for alleviating ACD-like symptoms induced by DNFB in the mouse.

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“…; Jung et al . ). Our report of the efficacy of CLA in this model suggests that CLA could have a potentially beneficial effect for the treatment of human allergic dermatitis.…”

Section: Discussionmentioning

confidence: 97%

Orally administered conjugated linoleic acid ameliorates allergic dermatitis induced by repeated applications of oxazolone in mice

Nakanishi

Tokunaga

Yamasaki

et al. 2016

Animal Science Journal

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Conjugated linoleic acid (CLA) is one of the constituents of animal products with possible health benefits such as anti-carcinogenic and anti-obesity effects. In this study, we investigated the immunomodulatory effects of CLA using a mouse model of allergic dermatitis. Mice were orally administered either a CLA mixture containing equal amounts of 9c, 11 t-CLA and 10 t, 12c-CLA, or high linoleic acid safflower oil, and allergic dermatitis was induced on the ear by repeated topical applications of oxazolone. Oral administration of the CLA mixture but not the high linoleic safflower oil attenuated the symptoms of allergic dermatitis in both ear weights and clinical scores. This effect was associated with decreased levels of ear interleukin-4 (IL-4) and plasma immunoglobulin E. The immunomodulatory effects of the CLA isomers were compared by an in vitro cytokine production assay. The results showed that 9c, 11 t-CLA, the most predominant isomer in animal products, significantly inhibited IL-4 and interferon-γ production from mouse splenocytes with similar potency to 10 t, 12c-CLA. These findings suggest that CLA, a constituent of animal products, has a potentially beneficial effect for amelioration of allergic dermatitis.

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Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Abstract: Dasatinib and LCB 03-0110 could be used as effective agents for the treatment of ACD without the adverse side-effect of skin atrophy.

Cited by 12 publications

References 50 publications

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

Extract ofRhus vernicifluaBark Suppresses 2,4-Dinitrofluorobenzene-Induced Allergic Contact Dermatitis

Orally administered conjugated linoleic acid ameliorates allergic dermatitis induced by repeated applications of oxazolone in mice

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