摘要:

AbstractKeratins are heteropolymeric proteins which form the intermediate filament cytoskeleton in epithelial cells. Since 1991. mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures. Epidermolysis bullosa simplex (EBS) was the First mechanobullous disease for which the underlying genetic lesion was found, with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma, resulting in skin fragility. The site of mutation in the keratin protein correlates with phenotypic severity in this disorder. Since mutations were identified in the basal cell keratins, the total number of keratin genes associated with diseases has risen to eleven. The rod domains of suprabasal keratins K1 and K 10 are mutated in bullous congenital ichthyosiform erythroderma (BC1E; also called epidermolytic hyperkeratosis, EH) and mosaicism for K 1/K 10 mutations results in a nevoid distribution of EH. An unusual mutation in the VI domain of K1 has also been found to cause diffuse non‐epidermolytic palmoplantar keratoderma (DNEPPK.). Mutations in palmoplantar specific keratin K9 cause epidermolytic palmoplantar keratoderma (EPPK) and mutations in the late differentiation suprabasal keratin K2e cause iehthyosis bullosa of Siemens (IBS). In the last year or so, mutations were discovered in differentiation specific keratins K6a and K16 causing pachyonychia congenita type 1 and K1 7 mutations occur in pachyonychia congenita type 2. K16 and K17 mutations have also been reported to produce phenotypes with little or no nail changes: K16 mutations can present as focal non‐epidermolytic palmoplantar keratoderma (NEPPK) and K17 mutations can result in a phenotype resembling steatocystoma multiplex. Recently, mutation of mucosal keratin pair K4 and K13 has been shown to underlie white sponge nevus (WSN). This year, the first mutations in a keratin‐associated protein, plectin, were shown to cause a variant of epidermolysis bullosa associated with late‐onset muscular dystrophy (MD‐EBS). An unusual mutation has been identified in K.5 which is responsible for EBS with mottled pigmentation and genetic linkage analysis suggests that the hair disorder monilethrix is likely to be due to a mutation in a hair keratin. The study of keratin diseases has led to a better understanding of the importance of the intermediate filament cytoskeleton and associated connector molecules in maintaining the structural integrity of the epidermis and other high stress epithelial tissues, as well as allowing diagnosis at the molecular level thus facilitating prenatal testing for this heterogeneous group of genod

ISSN:0906-6705    

DOI:10.1111/j.1600-0625.1996.tb00133.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractRecentin situstudies suggest the αvβ3integrin is a tumour progression marker in melanoma. We analyzed 5 human melanoma cell lines for their expression of the vitronectin binding αvβ3and αvβ5, integrins using flow cytometry. The role of these receptors in cell attachment, spreading and migration was investigated using attachment assays, video time lapse spreading and migration assays and with function blocking monoclonal antibodies. Cell lines derived from later stages of tumor progression exhibited high levels of αvβ3expression, whereas no similar correlation with αvβ5expression was identified. Cell attachment, spreading and migration response on vitronectin correlated well with the expression level of the αvβ3but not the αvβ5vitronectin receptor. Blocking of the αvβ3integrin resulted in a significant decrease in cell attachment, spreading and motility whereas the function blocking antibody against the αvβ5integrin only inhibited cell attachment in cell lines with the highest level of expression of this integrin. Taken together, our study indicates that the level of expression of the αvβ3and αvβ5integrins is heterogeneous in melanoma cell lines and that the αvβ5integrin, if present, may function only during the initial cell attachment whereas the αvβ3plays an important rôle in cell spreading

ISSN:0906-6705    

DOI:10.1111/j.1600-0625.1996.tb00134.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractIn certain pathological conditions, such as atopic dermatitis, interleukin‐4 (IL‐4) can be detected in the skin. As the rôle of this cytokine in inflammatory skin lesions is not completely clear, we investigated its biological effects on skin keratinocytes. It was found that freshly isolated as well as cultured keratinocytes obtained from normal individuals express mRNA for the IL‐4 receptor (IL‐4R) and produce IL‐4R protein, as determined by How cytometry. Moreover, IL‐4 induced a proliferative response in keratinocyles after 1 day of culture and enhanced B7/BB1 expression in these cells. B7‐2 (CD86) mRNA and protein were neither detected on untreated nor IL‐4 treated keratinocytes. In contrast to interferon‐γ (IFN‐γ), IL‐4 did not induce ICAM‐1 (CD54) or HLA‐DR‐expression. Keratinocytes which had been treated with IL‐4 showed an enhanced ability to stimulate allogeneic T‐cell proliferation in the presence of staphylococcus enterotoxin B (SEB),(p<0.01). Neutralizing anti‐ B7/BBI monoclonal antibodies did not block this effect. These results indicate that other molecules than B7/BB‐I, HLA‐DR or ICAM‐1 on IL‐4‐activated keratinocytes may be involved in T‐cell stimulation. In conclusion our results suggest, that locally produced IL‐4, besides modulating keratinocyte membrane molecules, may enable keratinoey

ISSN:0906-6705    

DOI:10.1111/j.1600-0625.1996.tb00135.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe objectives of this research were to determine whether melanotropin receptors are characteristic (constant) membrane markers of human melanoma cells. Methodologies were developed to visualize these receptors by fluorescence microscopy. Multiple copies (10–20) of both [Nle4.D‐Phe7]α‐MSH, a superpotent analog of α‐melanocyte stimulating hormone (α‐MSH). and a fluorophore, were conjugated to polyvinyl alcohol (PVA). Incubation in the presence of the multivalent macromolecular conjugate (FITC‐PVA‐MSH) resulted in binding of human epidermal melanocytes and keratinocytes and human melanoma cells (both melanotic and amelanotic) to the fluorescent conjugate. Binding of the conjugate to the cells exhibited a unique cluster pattern (capping) suggesting a receptor internalization related phenomenon. Most importantly, every cell of every melanoma cell line, melanotic or amelanotic. possessed receptors as visualized by fluorescence microscopy. Since the cells were not synchronized, some binding apparently took place during all phases of the cell cycle. Therefore, receptor expression appears not to be cell‐cycle dependent. Specificity of binding of FITC‐PVA‐MSH was demonstrated by several studies, (i) Binding of the conjugate to melanoma cells could be blocked by prior incubation of the cells in the presence of the unconjugated hormone analog: [Nle4,D‐Phe7]α‐MSH. (ii) The macromolecular conjugate lacking bound ligand (FITC‐PVA) did not bind to the melanoma cells, (iii) Another peptide, a substance‐P analog, attached to the substrate (FITC‐PVA‐SP) failed to bind to the cells, (iv) With the exception of keratinocytes, other cells of nonmelanocyte origin (e.g., fibroblasts, spleen, liver, kidney cells, and mammary cancer cells, lung cancer cells) did not bind to the conjugate. Thus, cell‐specific melanotropin receptors appear to be characteristic cell surface markers of epidermal melanocytes, keratinocytes, and melanoma cells. In several human melanoma cell lines these receptors appeared to be functional since [Nle4,α‐Phe7]α‐MSH stimulated tyrosinase activity. Fluorescent melanotropin conjugates might prove useful in determining whether all human melanoma (primary and metastatic) tumors possess such receptors. These receptors might then provide targets for melanotropic peptides for the identification,

ISSN:0906-6705    

DOI:10.1111/j.1600-0625.1996.tb00136.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractInvolvement of T‐lymphocytes in the pathogenesis of psoriasis and atopic dermatitis is well established. The question arises as to whether not only tissue infiltrating but also circulating T‐lymphocytes are involved in the disease process. Therefore we sought to determine whether T‐lymphocytes from patients with psoriasis and atopic dermatitis show abnormal biological behavior to the proinflammatory chemokine interleukin 8 (IL‐8)in vitroas studied by their chemotactic activity. In addition, the expression of T‐cell activation markers such as HLA‐DR and interleukin 2 receptor (IL‐2R) were analysed with FACS‐technique. In all, 25 patients with psoriasis (13 patients with severe psoriasis and 12 patients with mild psoriasis) and 11 patients with atopic dermatitis were investigated. For comparison, T‐lymphocytes from 14 healthy controls were tested equally. The results show that T‐cell chemotactic responses to IL‐8 were significantly decreased in patients with severe psoriasis as compared to healthy controls. T‐cells from patients with atopic dermatitis demonstrated an even more pronounced decrease in chemotactic response as compared to T‐cells from psoriasis patients or healthy controls. In contrast, increased expression of activation markers HLA‐DR and IL‐2R were demonstrated in circulating T‐cells from patients with severe psoriasis and atopic dermatitis in comparison to healthy controls. It can be concluded that circulating T‐cells in patients with severe psoriasis and atopic dermatitis show a decreasedin vitrochemotactic response to IL‐8. Furthermore, the in vivo phenotypic activation state of T‐lymphocytes in these patients seemed to be associated with their d

ISSN:0906-6705    

DOI:10.1111/j.1600-0625.1996.tb00137.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY