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  • ACTIVATION  (14)
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  • 1
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; human ; GENERATION ; SYSTEM ; DISTINCT ; PROTEIN ; PROTEINS ; cell line ; LINES ; ACTIVATION ; RESPONSES ; REDUCTION ; KERATINOCYTES ; SKIN ; CELL-LINES ; ISOFORM ; SUBUNIT ; Western-blot ; MEMBRANE ; CELL-LINE ; LINE ; CYTOCHROME-C ; EPITHELIAL-CELLS ; PROTEIN LEVELS ; western blot ; HaCaT ; MUCOSA ; HOST-DEFENSE ; DEFENSE ; human skin and oral epithelial cells,oxidoreductase,p67phox,spin trapping,superoxide radical ; NAD(P)H OXIDASE ; OXYGEN RADICALS ; P47(PHOX) ; SUPEROXIDE-PRODUCTION
    Abstract: In non-phagocytic cells, superoxide has been implicated in physiological and pathological cellular functions in the skin and mucosa, such as, host defense, mitogenic responses, and malignant conversion. Here, we identify a constitutively expressed heme-flavoprotein NADPH oxidase (Nox) system as a source of superoxide in human skin (HaCaT) and gingival mucosal (GM16) keratinocyte cell lines. Western blot analysis showed that both cell lines expressed the phagocyte oxidase (phox) cytosolic proteins Rac1, p40phox, and p67phox. With respect to the catalytic flavoheme protein subunit, HaCaT membranes, which expressed p22phox, showed an absorbance peak at 558 nm indicative of a b-type cytochrome. At mRNA levels, both GM16 and HaCaT cells expressed gp91phox homologs Nox1, Nox2, and Nox4, however, HaCaT cells expressed very low levels of Nox1 mRNA. At protein levels, Nox1 was readily detected in HaCaT but was nearly undetectable in GM16 cells. Consistently, Nox activity of HaCaT membranes was demonstrated by electron paramagnetic resonance spin-trapping and cytochrome c reduction, and the activity was sensitive to the flavoprotein inhibitor diphenylene iodonium. V-max values were 20-fold lower than those reported for phagocytic oxidase. In conclusion, keratinocytes expressed a Nox distinct from the phox isoform of phagocytes providing molecular evidence for a source of superoxide that may regulate cell proliferation and host defense in skin and oral mucosa
    Type of Publication: Journal article published
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; Germany ; THERAPY ; VITRO ; DISEASE ; DISEASES ; MICE ; ACTIVATION ; MECHANISM ; REDUCTION ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T cell activation ; T cells ; T-CELLS ; treatment ; MIGRATION ; RECRUITMENT ; ANTIGEN-PRESENTING CELLS ; C3H/HEJ MICE ; FOLLICLE ; SUBSET ; RE ; HAIR FOLLICLE ; LYMPHOID ORGANS ; REGULATORY T-CELLS ; DELAYED-TYPE HYPERSENSITIVITY ; RECOVERY ; HAIR LOSS ; lymph node ; LYMPH-NODE ; RELEVANCE ; AA ; autoimmune disease ; PROGRESS ; ACID DIBUTYLESTER SADBE ; ACTIVATED T-CELLS ; ATOPIC-DERMATITIS ; SKIN-ASSOCIATED CHEMOKINE
    Abstract: Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered. Allergen treatment of AA mice was not accompanied by a decrease in skin- infiltrating leukocytes or draining lymph node cells (LNC). However, the distribution of leukocyte subsets was changed with a dominance of monocytes in the skin and a reduced percentage of DCs in draining nodes. Chemokine and chemokine receptor expression in skin and draining nodes was strikingly increased and LNC from untreated and allergen-treated AA mice showed high migratory activity in vitro and readily homed in draining nodes and skin after intravenous injection. However, FITC labelling of the skin and subcutaneous transfer of dye-labelled DC revealed that allergen treatment created a chemokine milieu severely hampering DC migration from the skin towards the draining node. An allergic eczema. Induced reduction in DC migration and antigen transfer could well contribute to insufficient T-cell activation and the recovery of hair follicle in AA and possibly be of relevance for other skin- related autoimmune diseases
    Type of Publication: Journal article published
    PubMed ID: 16675965
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; proliferation ; CELL ; Germany ; INHIBITION ; VITRO ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; DRUG ; DIFFERENTIATION ; EPITHELIA ; ACTIVATION ; MARKER ; CONTRAST ; SKIN ; treatment ; ALPHA ; culture ; MATURATION ; CELL-DEATH ; ADHESION ; CELL-ADHESION ; RECEPTORS ; PROGRAMMED CELL-DEATH ; BARRIER FUNCTION ; TERMINAL DIFFERENTIATION ; AUTOIMMUNITY ; FUNCTIONAL-CHARACTERIZATION ; cell adhesion ; DRUGS ; ORGANOTYPIC COCULTURE ; cholinergic ; DARIERS-DISEASE ; KERATINOCYTE ADHESION ; NICOTINIC ACETYLCHOLINE-RECEPTOR ; PEMPHIGUS-VULGARIS
    Abstract: The aim of this study was to analyze the influence of cholinergic and anticholinergic drugs on epidermal physiology using organotypic cocultures (OTCs). Blocking of all acetylcholine receptors (AChRs) by combined treatment with mecamylamine and atropine or treatment with strychnine (blocking alpha 9nAChR) for 7-14 days resulted in a complete inhibition of epidermal differentiation and proliferation. Blockage of nicotinic (n) AChR with mecamylamine led to a less pronounced delay in epidermal differentiation and proliferation than blockage of muscarinic ( m) AChR with atropine, evidenced by reduced epithelial thickness and expression of terminal differentiation markers like cytokeratin 2e or filaggrin. In OTCs treated with atropine, mecamylamine, or strychnine, we could demonstrate intracellular lipid accumulation in the lower epidermal layers, indicating a severely disturbed epidermal barrier. In addition, we observed prominent acantholysis in the basal and lower suprabasal layers in mecamylamine-, atropine-, and strychnine-treated cultures, accompanied by a decreased expression of cell adhesion proteins. This globally reduced cell adhesion led to cell death via intrinsic activation of apoptosis. In contrast, stimulation of nAChR and mAChR with cholinergic drugs resulted in a significantly thickened epithelium, accompanied by an improved epithelial maturation. In summary, we show that epidermal AChR are crucially involved in the regulation of epidermal homeostasis
    Type of Publication: Journal article published
    PubMed ID: 16810300
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  • 4
    Keywords: CELLS ; ACTIVATION ; KERATINOCYTES ; SKIN ; CYCLE ; MIGRATION ; E6 ; E-cadherin ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; LIFE ; DNA LOADS
    Abstract: Human papillomaviruses (HPVs), which are contained in the alpha, beta, gamma, mu, and nu genera, differ in their oncogenic potential and their tropism for cutaneous or mucosal epidermis. Langerhans cells (LC), the only epidermal professional antigen-presenting cells, are readily detected in normal mucosal and cutaneous epithelium. The aim of this study is to determine whether LC loss, which has been reported for HPV16, occurs in other HPV genera and establish its significance in viral pathology. We found that, as for HPV16, LCs were reduced in lesions infected with high-risk mucosal (alpha 7 and alpha 9 species) and low-risk cutaneous (gamma and mu) types. Lesions infected with alpha 10 low-risk genital types had reduced LC but contained epidermal LC patches, coincident with dermis-localized regulatory T cells (T-regs). In contrast to other genera, LCs were common in the epidermis, and T-regs occupied the dermis of the potentially high-risk cutaneous beta-HPV type infected lesions. Therefore, LC loss in the infected lesions occurred irrespective of tropism or oncogenic potential of the HPV type. LC depletion in the HPV-infected epidermis may create an environment that is permissive for viral persistence and in HPV lesions in which LCs are found, the presence of typically immunosuppressive T-regs may compensate for their continued presence
    Type of Publication: Journal article published
    PubMed ID: 19759549
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  • 5
    Keywords: ANGIOGENESIS ; CANCER ; EXPRESSION ; INVASION ; proliferation ; SURVIVAL ; tumor ; CELL-PROLIFERATION ; MICROVESSEL DENSITY ; DENSITY ; GENE ; GENES ; TUMORS ; PATIENT ; ACTIVATION ; FAMILY ; prognosis ; PROGRESSION ; MUTATION ; metastases ; MELANOMA ; MUTATIONS ; ONCOGENE ; CHILDREN ; CUTANEOUS MELANOMA ; INITIATION ; BRAF ; N-RAS ; Ras ; neuroblastoma ; RE ; PATIENT SURVIVAL ; cell proliferation ; CODON ; CUTANEOUS MELANOMAS ; Ki-67 ; NEVI ; RAS MUTATIONS ; VERTICAL GROWTH-PHASE
    Abstract: Previous studies have shown frequent mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) or NRAS ( neuroblastoma RAS viral [V-ras] oncogene homolog) genes in cutaneous melanoma, but the relationship between these alterations and tumor cell proliferation has not been examined in human melanoma. In our study of 51 primary nodular melanomas and 18 paired metastases, we found mutations in BRAF ( codon 600, previously denoted 599) in 15 primary tumors (29%) and eight metastases (44%). The figures for NRAS mutations were 27% and 22%, respectively. Mutations in BRAF and NRAS genes were mutually exclusive in all but one case, and were maintained from primary tumors through their metastases. Mutations, however, were not associated with tumor cell proliferation by Ki-67 expression, tumor thickness, microvessel density, or vascular invasion, and there were no differences in patient survival. Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma
    Type of Publication: Journal article published
    PubMed ID: 16098042
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  • 6
    Keywords: CELLS ; EXPRESSION ; Germany ; DISEASE ; PROTEIN ; MICE ; ACTIVATION ; LIGAND ; RESPONSES ; MECHANISM ; MARKER ; REDUCTION ; RENAL-FUNCTION ; mechanisms ; T cell activation ; T cells ; T-CELLS ; treatment ; NUMBER ; Jun ; AUTOANTIBODIES ; SERUM ; AUTOIMMUNITY ; DISORDERS ; VERSUS-HOST-DISEASE ; CD40 LIGAND ; REGULATORY T-CELLS ; function ; LOSSES ; ONSET ; REDUCED EXPRESSION ; POSSIBLE MECHANISMS ; SHORT-TERM ; ATOPIC-DERMATITIS ; LUPUS-ERYTHEMATOSUS ; BROWN-NORWAY RATS ; TACROLIMUS OINTMENT ; TOPICAL TACROLIMUS
    Abstract: Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8+ T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses
    Type of Publication: Journal article published
    PubMed ID: 16470176
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  • 7
    Keywords: CANCER ; ACTIVATION ; SKIN ; INDUCED APOPTOSIS ; chemotherapy ; MUTATIONS ; MUTANT P53 ; SIMIAN-VIRUS-40 ; DNA-DAMAGE RESPONSE ; nutlin-3
    Abstract: Merkel cell carcinoma (MCC) is a rare and very aggressive skin cancer with viral etiology. The tumor-associated Merkel cell polyoma virus (MCV) belongs to a group of viruses encoding T antigens (TAs) that can induce tumorigenesis by interfering with cellular tumor-suppressor proteins like p53. To explore possible modes of p53 inactivation in MCC p53 sequencing, expression analysis and reporter gene assays for functional analyses were performed in a set of MCC lines. In one MCV-negative and one MCV-positive cell line, p53 inactivating mutations were found. In the majority of MCC lines, however, wild-type p53 is expressed and displays some transcriptional activity, which is yet not sufficient to effectively restrict cellular survival or growth in these cell cultures. Interestingly, the MCV TAs are not responsible for this critical lack in p53 activity, as TA knockdown in MCV-positive MCC cells does not induce p53 activity. In contrast, inhibition of the ubiquitin ligase HDM-2 (human double minute 2) by Nutlin-3a leads to p53 activation and p53-dependent apoptosis or cell cycle arrest in five out of seven p53 wild-type MCC lines, highlighting p53 as a potential target for future therapies of this aggressive tumor.
    Type of Publication: Journal article published
    PubMed ID: 23563200
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  • 8
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; tumor ; INHIBITION ; transcription ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; KERATINOCYTES ; PHOSPHORYLATION ; DEGRADATION ; NF-kappa B ; IL-8 ; DEATH RECEPTORS ; I kappa B ; IL-1Ra
    Abstract: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) exerts a potent cytotoxic activity especially against many tumor cell types such as transformed keratinocytes. The specific role of the different TRAIL receptors in this process, however, is unknown. In this report we examine the role the TRAIL receptors play in both the apoptotic and nonapoptotic responses of HaCaT keratinocytes to leucine zipper TRAIL (LZ- TRAIL). By employing receptor-specific blocking antibodies we demonstrate that TRAIL receptor 1 plays the primary role in mediating caspase activation and apoptosis in HaCaT cells. Furthermore, we show that this receptor mainly mediates nuclear factor kappaB activation and expression of the pro-inflammatory cytokine interleukin-8 and that nuclear factor kappaB activation is critically required for the induction of pro- inflammatory cytokines in response to LZ-TRAIL. Taken together, our data suggest that beside its potent pro-apoptotic role, LZ- TRAIL leads to pro-inflammatory responses that are mainly mediated by TRAIL receptor 1 in HaCaT keratinocytes
    Type of Publication: Journal article published
    PubMed ID: 12839575
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; FACTOR RECEPTOR ; Germany ; MODELS ; DISEASE ; MICE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; MARKER ; REDUCTION ; INDUCTION ; SKIN ; T-CELLS ; FREQUENCY ; SUSCEPTIBILITY ; cytokines ; DELETION ; MOUSE ; resistance ; MARKERS ; PATHOGENESIS ; LYMPHOCYTES ; RECRUITMENT ; INVOLVEMENT ; T-LYMPHOCYTES ; GROWTH-FACTOR-BETA ; RECEPTORS ; IL-2 ; INTERFERON-GAMMA ; inflammation ; INTERLEUKIN-2 ; FACTOR-BETA ; FACTOR RECEPTORS ; INFILTRATION ; targeted ; hair ; development ; DELAYED-TYPE HYPERSENSITIVITY ; LEVEL ; NECROSIS-FACTOR ; alopecia areata ; CD8(+) CELLS ; experimental mouse model ; HAIR LOSS ; interieukin-2 ; TUMOR NECROSIS FACTOR
    Abstract: Alopecia areata (AA) is an autoimmune hair loss disease, that can be transferred between C3H/HeJ mice by skin grafting. We explored whether AA susceptibility is influenced by the availability of interleukin (IL)-2, a cytokine with leukocyte activating and regulatory properties. Mice heterozygous for a targeted deletion of IL-2 from the histocompatible C3.129P2(B6)-II2(tm1Hor) substrain, that produce reduced levels of IL-2, were examined for AA development after grafting skin from AA-affected C3H/HeJ mice. After grafting, nine of 19 (47%) heterozygous IL-2(+/-) versus 16 of 18 (88%) IL-2(+/+) wild-type littermates developed AA. Although dense follicular leukocyte infiltrates were apparent in AA affected wild-type mice, AA-developing IL-2(+/-) littermates had a reduced leukocyte infiltration, and AA-resistant IL-2 mice had no inflammation. Lymph node cell analysis revealed a reduction in leukocyte activation markers in AA-developing IL-2(+/-) mice. IL-2(+/-) mice presented with low level expression of cytokines (IL-4, IL-10, interferon-gamma, transforming growth factor-beta), upregulation of tumor necrosis factor receptors, and increased leukocyte apoptosis susceptibility independent of AA expression. In the skin, CD4(+) cells and monocytes were reduced; activation markers were not upregulated and very few CD44v3(+) or CD44v10(+) leukocytes were recovered. Taken together, our data suggest that AA resistance of IL-2(+/-) mice is because of the failure of activated leukocyte recruitment, thus pointing toward an involvement of IL-2 in AA pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 16297194
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  • 10
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; Germany ; VITRO ; SYSTEM ; transcription ; DIFFERENTIATION ; TISSUE ; MICE ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; SKIN ; C-JUN ; fibroblasts ; treatment ; SIGNAL ; TRANSGENIC MICE ; STRESS ; REPAIR ; EPITHELIAL-CELLS ; KINETICS ; REGULATOR ; COLONY-STIMULATING FACTOR ; INTERCELLULAR COMMUNICATION ; TISSUE-SPECIFIC EXPRESSION ; inflammation ; CYTOKINE ; FAMILIES ; MICE LACKING ; KERATINOCYTE DIFFERENTIATION ; IMMUNE-SYSTEM ; LEVEL ; REGULATED GENE ; macrophage ; inflammatory cells ; COLLAGEN GEL ; GROWTH-STIMULATORY ACTIVITY ; TRANSCRIPTION FACTOR AP-1
    Abstract: The cutaneous response to injury and stress comprises a temporary change in the balance between epidermal proliferation and differentiation as well as an activation of the immune system. Soluble factors play an important role in the regulation of these complex processes by coordinating the intercellular communication between keratinocytes, fibroblasts, and inflammatory cells. In this study, we demonstrate that JunB, a member of the activator protein-1 transcription factor family, is an important regulator of cytokine expression and thus critically involved in the cutaneous response to injury and stress. Mice lacking JunB in the skin develop normally, indicating that JunB is neither required for cutaneous organogenesis, nor homeostasis. However, upon wounding and treatment with the phorbol ester 12-O-decanoyl-phorbol-13-acetate, JunB-deficiency in the skin likewise resulted in pronounced epidermal hyperproliferation, disturbed differentiation, and prolonged inflammation. Furthermore, delayed tissue remodelling was observed during wound healing. These phenotypic skin abnormalities were associated with JunB-dependent alterations in expression levels and kinetics of important mediators of wound repair, such as granulocyte macrophage colony-stimulating factor, growth-regulated protein-1, macrophage inflammatory protein-2, and lipocalin-2 in both the dermal and epidermal compartment of the skin, and a reduced ability of wound contraction of mutant dermal fibroblasts in vitro
    Type of Publication: Journal article published
    PubMed ID: 16439969
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