oxazolone and Psoriasis

The interleukin 7 receptor alpha chain (IL-7Rα) is predominately expressed by lymphocytes, and activation by its ligand IL-7 supports the development and maintenance of T cells and boosts T-cell mediated immunity. We recently reported that lymphatic endothelial cells (LECs) in dermal lymphatics also express IL-7 and its receptor chains (IL-7Rα and CD132) and that IL-7 supports lymphatic drainage. This suggested that activation of IL-7Rα signaling in lymphatics could exert inflammation-resolving activity, by promoting the clearance of excess tissue fluid. Here we investigated how the potentially opposing effects of IL-7Rα signaling in immune cells and in the lymphatic vasculature would affect the development and progression of psoriasis-like skin inflammation. We found that during acute and chronic skin inflammation mice with an endothelial-specific deletion of IL-7Rα (IL-7Rα

Topics: Animals; Antibodies, Neutralizing; CD4-Positive T-Lymphocytes; Disease Models, Animal; Endothelial Cells; Female; Gene Expression Regulation; Humans; Imiquimod; Inflammation; Interleukin-7; Lymph Nodes; Lymphatic Vessels; Male; Mice; Mice, Inbred C57BL; Organ Specificity; Oxazolone; Psoriasis; Receptors, Interleukin-7; Signal Transduction; Skin; Tetradecanoylphorbol Acetate

Contact dermatitis and psoriasis are skin disorders caused by immune dysregulation, yet much remains unknown about their underlying mechanisms. Ghrelin, a recently discovered novel peptide and potential endogenous anti-inflammatory factor expressed in the epidermis, is involved in skin repair and disease. In this study, we investigated the expression pattern and therapeutic effect of ghrelin in both contact dermatitis and psoriasis mouse models induced by oxazolone (OXA) and imiquimod (IMQ), respectively, and in TNF-α-stimulated RAW264.7 macrophages, NHEKs and skin fibroblasts. Ghrelin expression was reduced in both the OXA-induced contact dermatitis and IMQ-induced psoriasis mouse models. Furthermore, treatment with ghrelin attenuated skin inflammation in both the contact dermatitis and psoriasis mouse models. Mice administered PBS after OXA- or IMQ-induced model generation exhibited typical skin inflammation, whereas ghrelin treatment in these mouse models substantially decreased the dermatitis phenotype. In addition, exogenous ghrelin attenuated the inflammatory reaction induced by TNF-α in RAW264.7 cells. Moreover, ghrelin administration limited activation of NF-κB signaling. In summary, ghrelin may represent a potential molecular target for the prevention and treatment of inflammatory skin diseases, including contact dermatitis and psoriasis.

Topics: Animals; Dermatitis, Contact; Disease Models, Animal; Fibroblasts; Gene Expression Regulation; Ghrelin; Humans; Imiquimod; Immune System Diseases; Inflammation; Mice; NF-kappa B; Oxazolone; Psoriasis; RAW 264.7 Cells; Signal Transduction; Skin; Tumor Necrosis Factor-alpha

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.

Topics: ADAM17 Protein; Administration, Topical; Animals; Drug Design; Enzyme Inhibitors; Female; Humans; Hydroxamic Acids; Mice; Mice, Hairless; Microsomes, Liver; Oxazolone; Psoriasis; Skin Diseases; Solubility; Sulfonamides; Tumor Necrosis Factor-alpha

Topics: Aminoquinolines; Animals; Case-Control Studies; Dermatitis, Contact; Female; Humans; Imiquimod; Male; Mice; Oxazolone; Psoriasis; Receptors, Interleukin

Cathepsin S (CATS) is a cysteine protease, well known for its role in MHC class II-mediated antigen presentation and extracellular matrix degradation. Disturbance of the expression or metabolism of this protease is a concomitant feature of several diseases. Given this importance we studied the localization and regulation of CATS expression in normal and pathological human/mouse skin. In normal human skin CATS-immunostaining is mainly present in the dermis and is localized in macrophages, Langerhans, T- and endothelial cells, but absent in keratinocytes. In all analyzed pathological skin biopsies, i.e. atopic dermatitis, actinic keratosis and psoriasis, CATS staining is strongly increased in the dermis. But only in psoriasis, CATS-immunostaining is also detectable in keratinocytes. We show that cocultivation with T-cells as well as treatment with cytokines can trigger expression and secretion of CATS, which is involved in MHC II processing in keratinocytes. Our data provide first evidence that CATS expression (i) is selectively induced in psoriatic keratinocytes, (ii) is triggered by T-cells and (iii) might be involved in keratinocytic MHC class II expression, the processing of the MHC class II-associated invariant chain and remodeling of the extracellular matrix. This paper expands our knowledge on the important role of keratinocytes in dermatological disease.

Topics: Animals; Biopsy; Cathepsins; Cell Communication; Cell Line; Coculture Techniques; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Keratinocytes; Major Histocompatibility Complex; Mice; Oxazolone; Psoriasis; T-Lymphocytes; Up-Regulation

Xanthohumol (XN) and its related compounds were evaluated for their effects on modulating the production of interleukin (IL)-12, the most important factor driving T helper 1 immune responses. XN showed the strongest inhibitory effect on IL-12 production in macrophages stimulated by lipopolysaccharide (LPS) or LPS/interferon-gamma. Xanthohumol 4'-O-beta-D-glucopyranoside (XNG) inhibited IL-12 production less effectively than XN. Isoxanthohumol and 8-prenylnaringenin showed comparatively lower inhibitory effects on IL-12 production than XNG. (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside did not exert any effect on IL-12 production. We then tested how these compounds affected NF-kappaB binding activity to the kappaB site in the nucleus. The compounds inhibited kappaB binding in macrophages with the same potency order as IL-12 inhibition. Furthermore, we investigated whether XN, which showed the most effective reduction of IL-12 production, attenuated skin inflammation. Chronic allergic contact dermatitis, an experimental model for psoriasis, was used to determine the anti-inflammatory effects of XN in vivo. XN treatment reduced the degree of ear thickening induced by oxazolone. Taken together, XN might be effective as an anti-inflammatory agent to reduce skin inflammation by inhibiting IL-12 production.

Topics: Animals; Cells, Cultured; Chronic Disease; Dermatitis, Allergic Contact; Female; Flavonoids; Humans; Interferon-gamma; Interleukin-12; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Animal; NF-kappa B; Oxazolone; Propiophenones; Protein Binding; Psoriasis

While psoriasis is one of the most common skin disorders in humans, effective, safe and inexpensive treatments are still largely unavailable. Chinese herbal medicine (CHM) has been used for centuries for treating psoriasis and several reports claim that systemic administration of one such CHM, Tuhuai, mainly composed of flos sophorae, smilax glabra roxb and licorice, is effective in psoriasis. However, the mechanisms by which this CHM improves psoriasis are not yet clear. Two universal features of psoriasis are epidermal hyperplasia and inflammation. Moreover, drugs that specifically inhibit epidermal hyperplasia and/or inflammation are widely used to treat psoriasis. Here, we investigated whether topical applications of Tuhuai extract exhibit anti-proliferative and anti-inflammatory activities in two murine models of inflammatory dermatoses. To assess Tuhuai's potential anti-proliferative effect, we disrupted epidermal barrier function twice-daily for 4 days in normal hairless mice followed by topical applications of either 1% Tuhuai extract or Vehicle to both flanks immediately after each barrier perturbation. Changes in epidermal proliferation and apoptosis were evaluated by immunohistochemistry and TUNEL staining. To assess the anti-inflammatory effects of Tuhuai, both irritant (phorbol ester) and acute allergic contact dermatitis (oxazolone) models were used. Whereas topical Tuhuai extract did not alter epidermal proliferation or induce irritation in normal skin, it both reduced epidermal hyperplasia in the epidermal hyperproliferative model, and reduced inflammation in both irritant and allergic contact dermatitis models. As topical Tuhuai extract exhibits anti-proliferative and anti-inflammatory properties in a variety of human models of inflammatory dermatoses, Tuhuai could provide an effective, relatively safe and inexpensive therapeutic alternative for the treatment of inflammatory dermatoses, including psoriasis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Proliferation; Dermatitis, Allergic Contact; Dermatitis, Contact; Disease Models, Animal; Drugs, Chinese Herbal; Fabaceae; Female; Glycyrrhiza; Humans; Hyperplasia; Male; Mice; Mice, Hairless; Oxazolone; Phytotherapy; Psoriasis; Skin; Smilax; Tetradecanoylphorbol Acetate

During the screening program to discover antipsoriatic agents from natural products, ginseng was found to show inhibitory activity in oxazolone-induced mouse ear dermatitis. Therefore, the effects of a main constituent ginsenoside Rb1 isolated from ginseng and its metabolite compound K on oxazolone-induced mouse ear dermatitis were investigated. Compound K at concentrations of 0.02% and 0.05% also potently suppressed mouse ear swelling by 54% and 76% at 16 days, respectively, although ginsenoside Rb1 did not significantly show the inhibitory activity. The compound K also significantly reduced the levels of mRNA of cyclooxygenase (COX)-2, IL-1beta, TNF-alpha, IFN-gamma and IL-4 increased in oxazolone-applied mouse ears. Based on these findings, the compound K may improve contact dermatitis or psoriasis by the regulation of COX-2 produced by macrophage cells and interferon-gamma and IL-4 induced by Th cells.

Topics: Animals; Cell Line; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Contact; Dinoprostone; Female; Ginsenosides; Macrophages; Membrane Proteins; Mice; Mice, Inbred ICR; Nitric Oxide; Oxazolone; Prostaglandin-Endoperoxide Synthases; Psoriasis; RNA, Messenger