Avarol inhibits TNF-α generation and NF-κB activation in human cells and in animal models

Skin plays an essential role in protecting the body's internal environment against environmental insults. Keratinocyte differentiation, including expression of such cornified envelope proteins as involucrin (INV) and loricrin, is essential to maintain the structure and function of the epidermis. Disruption of the expression of these proteins causes epidermal dysplasia and dysfunction. 1,2) Treating skin with 12-O-tetradecanoylphorbol-13-acetate (TPA) causes epidermal hyperplasia through an abnormal increase in cornified envelope protein levels.3) TPA is thought to produce these effects by inducing protein kinase C (PKC) activation, calcium influx, and release of inflammatory cytokines, for example. [4][5][6] The precise mediators of TPA signaling that cause epidermal hyperplasia, however, remain unclear.Cholesterol sulfate (CS) is a chemical mediator that maintains epidermal homeostasis. Accumulation of CS-for instance, owning to a deficiency in the catabolic enzyme steroid sulfatase (SSase)-causes dyskeratosis.7-9) Levels of the CS biosynthetic enzyme cholesterol sulfotransferase (Ch-ST) are also associated with the extent of epidermal differentiation. In particular, St2b2, a member of the cytosolic sulfotransferase family, is the primary Ch-ST in mouse epidermis, 10) where it plays a role in the expression of INV. 11)Ch-ST activity increases together with cornified envelope protein levels after TPA treatment. 12,13) Thus, St2b2 may be linked to TPA-induced epidermal hyperplasia. Expressed beginning at early cornification, INV is involved in construction of the cornified envelope.14,15) Overexpression of INV distorts the structure of the epidermis.1,16) Furthermore, cells that express INV in response to various stimuli are selectively expelled from the basal layer composed of uncornified epidermal cells. 17) Thus, INV expression levels can be used as a marker of the extent of epidermal differentiation.Application of TPA on mouse skin causes an intense inflammatory response. The associated signaling is mediated by various cytokines and regulatory factors, such as tumor necrosis factor-alpha (TNFa) and interleukins, which are involved in epidermal differentiation and dyskeratosis. 18,19) Indeed, TNFa levels increase when epidermis is exposed to TPA.20,21) TNFa binding to TNF receptor (TNFR) results in activation of a number of transcription factors, including nuclear factor-kappa B (NF-kB). Moreover, treating keratinocytes with anti-inflammatory drugs suppresses TPAinduced increases in Ch-ST activity, 13,22) suggesting that TNFa-NF-kB signaling mediates TPA-induced enhancement of St2b2 expression.The present study shows that TNFa-NF-kB signaling contributes to TPA-induced epidermal hyperplasia via increased St2b2 expression. MATERIALS AND METHODS Materials Cholesterol, CS, 3Ј-phosphoadenosine-5Ј-phos-

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“…[32][33][34] In the present study, an NF-kB inhibitor suppressed TNFa-induced expression of cornified envelope proteins and St2b2 (Fig. 12).…”

Section: Discussionsupporting

confidence: 56%

Tumor Necrosis Factor-Alpha-Nuclear Factor-Kappa B-Signaling Enhances St2b2 Expression during 12-O-Tetradecanoylphorbol-13-acetate-Induced Epidermal Hyperplasia

Matsuda

Shimada

Sato

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Accumulating data show that the TNF-α-mediated upregulation of iNOS, IL-6 and IL-8 depends on MAPKs and NF-κB pathways (Cho et al 2007;Amigo et al 2008). However, whether the effect of H 2 S is exerted through inhibiting MAPKs and NF-κB is unknown yet.…”

Section: Effects Of H 2 S On Tnf-α-mediated Activation Of Mapks and Nmentioning

confidence: 99%

Psoriasis Is Associated with Low Serum Levels of Hydrogen Sulfide, a Potential Anti-inflammatory Molecule

Alshorafa

Guo

Zeng

et al. 2012

Tohoku J. Exp. Med.

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Psoriasis, characterized by circumscribed, red, thickened plaques with an overlying silver-white scale, is a common T-cell-mediated chronic inflammatory skin disease. Although hydrogen sulfide (H 2 S) has been shown to be a signaling molecule with both pro-or anti-inflammatory effects, its relationship with psoriasis has not been elucidated. In the present study, 15 patients with chronic progressive psoriasis and 15 healthy volunteers were investigated. Serum H 2 S levels in psoriasis patients were significantly lower than those of healthy controls (16.69 ± 5.47 μM vs. 34.5 ± 6.39 μM). In contrast, serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly higher in psoriasis patients than healthy controls (22.88 ± 6.24 pg/ml vs. 12.07 ± 3.68 pg/ml; 61.47 ± 8.21 pg/ml vs. 31.54 ± 13.73 pg/ml; and 39.43 ± 8.56 pg/ml vs. 20.55 ± 6.45 pg/ml, respectively). The serum H 2 S levels negatively correlated with clinical disease severity. Furthermore, treatment of HaCaT human keratinocytes with TNF-α increased the levels of nitric oxide (NO), IL-6 and IL-8 (32.21 ± 5.71 μM vs. 3.22 ± 0.98 μM; 203.96 ± 13.16 pg/ml vs. 13.57 ± 3.75 pg/ml; and 301.24 ± 30.17 pg/ml vs. 29.06 ± 10.91 pg/ml, respectively) in the culture media. Exogenous H 2 S inhibited the TNF-α -mediated upregulation of NO, IL-6 and IL-8 in a dosedependent manner. In addition, H 2 S inhibited TNF-α-mediated activation of p38, extracellular-signalregulated kinase and nuclear factor kappa B. In conclusion, H 2 S may play a protective role in the pathogenesis of psoriasis. H 2 S-releasing agents may be promising therapeutics for psoriasis.

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“…Marine natural products, in particular, have recently been recognized as a promising source of NF-B inhibitors [20,23,24]. With the aim to find new potent NF-B inhibitors, we screened 220 extracts from Fijian marine organisms including algae, sponges, cnidarians, ascidians, and echinoderms collected by the Institute of Applied Sciences (IAS) Marine Collection (University of the South Pacific, Suva, Fiji) between 1997 and 2003.…”

Section: Introductionmentioning

confidence: 99%

The inhibition of TNF-α-induced NF-κB activation by marine natural products

Folmer

Jaspars

Solano

et al. 2009

Biochemical Pharmacology

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, et al.. The inhibition of TNF-α induced NF-κB activation by marine natural products. Biochemical Pharmacology, Elsevier, 2009, 78 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 AbstractThe deregulated activation of NF-B is associated with cancer development and inflammatory diseases. With the aim to find new NF-B inhibitors, we purified and characterized compounds from extracts of the Fijian sponge Rhabdastrella globostellata, the crinoid Comanthus parvicirrus, the soft corals Sarcophyton sp. nov. and Sinularia sp., and the gorgonian Subergorgia sp. after an initial screening of 266 extracts from different marine origins.Results obtained show that selected purified compounds had a cytotoxic effect on the human leukaemia cell line K562, inhibited both TNF--induced NF-B-DNA binding as well as TNF- induced IB degradation and nuclear translocation of p50/p65. Furthermore, we observed inhibition of NF-B activation induced by an overexpression of TNFR1, TRAF2, TRADD, or IKK Interestingly, natural products inhibited IKK kinase as well as the 26S proteasome proteolytic activity.

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Avarol inhibits TNF-α generation and NF-κB activation in human cells and in animal models

Cited by 32 publications

References 48 publications

Tumor Necrosis Factor-Alpha-Nuclear Factor-Kappa B-Signaling Enhances St2b2 Expression during 12-O-Tetradecanoylphorbol-13-acetate-Induced Epidermal Hyperplasia

Tumor Necrosis Factor-Alpha-Nuclear Factor-Kappa B-Signaling Enhances St2b2 Expression during 12-O-Tetradecanoylphorbol-13-acetate-Induced Epidermal Hyperplasia

Psoriasis Is Associated with Low Serum Levels of Hydrogen Sulfide, a Potential Anti-inflammatory Molecule

The inhibition of TNF-α-induced NF-κB activation by marine natural products

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