Role of AhR/ARNT system in skin homeostasis Furue, Masutaka; Takahara, Masakazu; Nakahara, Takeshi ...
Archives of Dermatological Research,
11/2014, Letnik:
306, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to structurally diverse synthetic and naturally occurring chemicals including dioxins, flavonoids, tryptophan ...photoproducts, and
Malassezia
metabolites. Upon binding to its ligands, cytoplasmic AhR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological and toxicological effects by inducing the transcription of various AhR-responsive genes. AhR ligation controls oxidation/antioxidation, epidermal barrier function, photo-induced response, melanogenesis, and innate immunity. This review summarizes recent advances in the understanding of the regulatory mechanisms of skin homeostasis mediated by the AhR/ARNT system.
Abstract Background Benzo(a)pyrene (BaP) is an environmental contaminant found in cigarette smoke. It is well known that cigarette smoking exacerbates interleukin-8 (IL-8)-related inflammatory skin ...diseases such as psoriasis, palmoplantar pustulosis and acne. Although BaP has been shown to exert its biological effects via the aryl hydrocarbon receptor (AhR) signaling pathway, the mechanism of its inflammatory effects on skin remains unanswered. Objective To elucidate whether or not BaP cause AhR activation and subsequent oxidative stress leading to IL-8 production in normal human epidermal keratinocytes (NHEKs). Methods NHEKs exposed to BaP were analyzed. Immunofluorescence, real-time PCR, Western blotting, ELISA, reactive oxygen species (ROS) detection using H2DCFDA and RNA interference using si (small interfering) RNA were employed. Results Immunofluorescence analysis clearly demonstrated that BaP induced nuclear translocation of AhR from cytoplasm. The AhR activation subsequently induced CYP1A1 mRNA and protein expression in a dose-dependent manner. In addition, ROS and IL-8 production were coordinately augmented by BaP, whereas this was not the case in IL-1α, IL-6, TNF-α or GM-CSF production. Knockdown of AhR expression using siRNA transfection inhibited BaP-induced-ROS and IL-8 production, suggesting that these responses are strongly dependent on the AhR signaling pathway. Furthermore, the addition of N-acetyl cystein or catalase cancelled the IL-8 production by BaP, indicating that ROS production is essential for IL-8 production. Results This data highlights AhR-ROS-dependent regulation of IL-8 in NHEKs by BaP, providing a plausible explanation, at least in part, for why cigarette smoking exacerbates IL-8-related skin diseases such as psoriasis, palmoplantar pustulosis and acne.
Ketoconazole (KCZ) has been shown to exhibit anti-inflammatory effects in addition to its inhibitory effects against fungi; however, the underlying molecular mechanism remains poorly understood. Aryl ...hydrocarbon receptor (AhR), a receptor that is activated by polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons such as dioxin, is a sensor of the redox system against oxidative stress and regulates nuclear factor-erythroid 2-related factor-2 (Nrf2), a master switch of the redox machinery. To clarify whether KCZ modulates AhR-Nrf2 function leading to redox system activation, cultured human keratinocytes were treated with KCZ. Confocal microscopic analysis revealed that KCZ induced AhR nuclear translocation, resulting in the upregulation of CYP1A1 mRNA and protein expression. Furthermore, KCZ actively switched on Nrf2 nuclear translocation and quinone oxidoreductase 1 expression. Tumor necrosis factor-α- and benzo(a)pyrene (BaP)-induced reactive oxidative species (ROS) and IL-8 production were effectively inhibited by KCZ. Knockdown of either AhR or Nrf2 abolished the inhibitory capacity of KCZ on ROS and IL-8 production. In addition, KCZ-induced Nrf2 activation was canceled by AhR knockdown. Moreover, KCZ inhibited BaP-induced 8-hydroxydeoxyguanosine and IL-8 production. In conclusion, the engagement of AhR by KCZ exhibits the cytoprotective effect mediated by the Nrf2 redox system, which potently downregulates either cytokine-induced (AhR-independent) or PAH-induced (AhR-dependent) oxidative stress.
•Artichoke is known for its antioxidant and anti-inflammatory activities.•Cynaropicrin is a major bioactive phytochemical in the artichoke.•Cynaropicrin activates AhR–Nrf2–Nqo1 antioxidant ...pathway.•Antioxidant cynaropicrin attenuates ultraviolet B-induced oxydation in keratinocytes.•Antioxidant cynaropicrin potently inhibits the production of IL-6 and TNFα.
Due to its antioxidant and anti-inflammatory activities, artichoke (Cynara scolymus) has been used as folk medicine to treat various diseases. Cynaropicrin (Cyn), a sesquiterpene lactone, is the major bioactive phytochemical in the artichoke; however, its pharmacological mechanism remains unknown. Because some phytochemicals exert their antioxidant activity by activating aryl hydrocarbon receptor (AhR), leading to subsequent induction of the antioxidant pathway including nuclear factor E2–related factor 2 (Nrf2) and NAD(P)H:quinone oxidoreductase 1 (Nqo1), we investigated whether Cyn also activates the AhR–Nrf2–Nqo1 pathway. Cyn indeed induced the activation (nuclear translocation) of AhR, leading to nuclear translocation of Nrf2 and dose-dependent upregulation of Nrf2 and Nqo1 mRNAs in human keratinocytes. The Cyn-induced AhR–Nrf2–Nqo1 activation was AhR- and Nrf2-dependent, as demonstrated by the observation that it was absent in keratinocytes transfected by siRNA against either AhR or Nrf2. In accordance with these findings, Cyn actively inhibited generation of reactive oxygen species from keratinocytes irradiated with ultraviolet B (UVB) in a Nrf2-dependent manner. Cyn also inhibited the production of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor-α from UVB-treated keratinocytes. Our findings demonstrate that Cyn is a potent activator of the AhR–Nrf2–Nqo1 pathway, and could therefore be applied to prevention of UVB-induced photo aging.
Abstract Background Special AT-rich sequence-binding protein-1 (SATB1), a new type of gene regulator, has been reported to be expressed in several human cancers and may have malignant potential. ...However, no data on SATB1 expression and its relationship to tumor progression in cutaneous malignant melanoma (CMM) has yet been reported. Objective We examined the immunohistochemical expression of SATB1 in CMM to determine whether it could serve as a prognostic marker. Methods A total of 97 samples of primary CMM and controls were immunostained for SATB1. The following clinicopathologic variables were evaluated: age, gender, subtype, SATB1 expression, Breslow thickness, Clark level, presence of ulceration, lymph node metastasis, distant metastasis, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan–Meier method and Cox proportional-hazards model. Results Forty cases (85.1%) of CMM showed positive staining for SATB1 by immunohistochemistry. The intensity of SATB1 staining was significantly higher in CMM than in nevus NV and normal skin (NS) ( P < 0.01). High SATB1 expression was significantly correlated with Breslow thickness, Clark level, mortality, presence of ulceration, and lymph node metastasis ( P < 0.01). Moreover, Kaplan–Meier analysis revealed that SATB1 overexpression was significantly associated with worse survival ( P < 0.01). Further univariate analysis and multivariate regression analysis indicated that SATB1 expression was an independent prognostic marker for CMM ( P = 0.03). Conclusions The overexpression of SATB1 correlated with metastatic potential of CMM and is a novel independent prognostic marker for predicting outcome.
Soybean tar Glyteer (Gly) has been widely used for the treatment of various inflammatory skin diseases in Japan since 1924 as an alternative to coal tar remedy. Recently, coal tar has been shown to ...induce barrier repair in atopic dermatitis via aryl hydrocarbon receptor (AhR). In this study, we demonstrated that Gly activated AhR by inducing its cytoplasmic to nuclear translocation in keratinocytes. The AhR ligation by Gly was biologically active, with significant and dose‐dependent upregulation of CYP1A1 expression, which is a specific marker for AhR activation. Gly upregulated the expression of filaggrin in an AhR‐dependent manner because its enhancing effect was completely abrogated in AhR‐knockdown keratinocytes. T‐helper (Th)2 cytokines inhibited the expression of filaggrin; however, Gly completely restored the Th2‐mediated inhibition of filaggrin expression. Furthermore, Gly coordinately upregulated a series of epidermal differentiation complex genes, including involucrin, loricrin and hornerin. In addition, Gly exhibited potent antioxidant activity through the activation of nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) and downstream antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 (Nqo1), which actually inhibited the generation of reactive oxygen species in keratinocytes treated with tumor necrosis factor‐α or benzoαpyrene. In conclusion, antioxidant Gly rescues the downregulated expression of filaggrin (and plausibly other barrier proteins) in a Th2‐skewed milieu via AhR activation, which may partly explain its empirical anti‐inflammatory therapeutic effects.
Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe ...burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures.
Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in ...animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzoαpyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.
Abstract Background Despite our growing knowledge regarding the biology of S100 family proteins in cancers and internal diseases, limited data are available with their distribution in normal skin and ...in sweat gland tumors. Objective To study the expression and distribution pattern of multiple S100 proteins in normal skin and in the tumors of sweat glands. Methods Immunohistological staining was performed using S100A2, S100A4, S100A6, S100A7, S100A8/9, S100A11, and S100P in 41 cases of various kinds of sweat gland tumors and in 13 cases of normal skin. Results In normal skin, S100A2, S100A6, S100A7, and S100P staining were observed in the sweat glands. S100A2 positively stained in the outer layer of the eccrine duct. S100A6 immunolabeling was observed in the secretory portion of the eccrine gland. Myoepithelial cells of the apocrine gland were positive for S100A2 and S100A6. S100A7 was positive in the acrosyringium, ductal, and secretory portions of the eccrine gland and in the inner layer of the apocrine gland. Intense S100P staining was detected in the inner layer of the acrosyringium and eccrine ducts. Langerhans cells and melanocytes showed strong immunoreactivity to S100A4. Extramammary Paget's disease (EMPD) expressed S100A7 and S100P with partial S100A6 and S1004 staining. Eccrine poroma expressed S100A2 and S100A7 with partial labeling with S100A6. Syringoma expressed S100A2, S1007, and S100P. Apocrine hidrocystoma expressed S100A2 with partial S100A6 and S100A7 immunoreactivity. Syringocystadenoma papilliferum expressed S100A2, S100A6, S100A7, and S100P. Conclusion S100A2, S100A6, S100A7, and S100P proteins are specifically involved in structure-related distribution and are potentially useful for differential diagnoses of sweat gland tumors.
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