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T A Luger

Publications and source records attributed to T A Luger.

At least 145 records · Page 8Linked to original sources
PubMed1995

Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity.

Whereas epidermal Langerhans cells (LC) are thought to be the principal APCs for initiation of contact hypersensitivity (CHS) responses, their role as APC in the effector phase of CHS is still unclear. It is currently thought that LC elicit the CHS response by presenting Ag to trafficking Ag-specific T cells within the skin. To test this hypothesis, we removed the majority of resident LC at the site of CHS challenge by topical application of various steroid creams to one ear in BALB/c mice (> 85% LC depletion). Either 2 days before or 4 days after steroid treatment of the ear, mice were sensitized on the abdomen with the hapten trinitrophenyl and challenged 10 days later at the steroid-pretreated ear. At that time point, direct anti-inflammatory effects of the steroid were no longer present. Surprisingly, CHS responses were markedly stronger at the sites of prior steroid application when compared with vehicle-treated controls, indicating that depletion of most of the resident LC not only fails to impair, but enhances, the expression of CHS significantly. UV irradiation or application of croton oil at the challenge site, as well as systemic steroid application, all of which are alternative methods of diminishing the number of epidermal LC, also significantly up-regulated CHS. In contrast, irritant dermatitis and sensitization or elicitation of CHS in steroid-treated mice at distant sites, as well as delayed-type hypersensitivity responses against the same hapten, were unaffected by topical steroid pretreatment. In conclusion, our data suggest that resident LC are not the relevant APC in the effector phase of CHS and that they may even provide down-regulatory, rather than stimulatory, signals during elicitation of CHS.

Administration, Topical↗
PubMed1995

Splicing variants of the human growth hormone mRNA: detection in pituitary, mononuclear cells and dermal fibroblasts.

The human growth hormone/human chorionic somatomammotropin (hGH/hCS) gene cluster contains five genes: hGH-N, hGH-V, hCS-B, and hCS-L. In this study, the nature of splicing products of their primary transcripts (except hCH-L) was analyzed by nuclease mapping as well as by reverse transcription-polymerase chain reaction (RT-PCR) experiments All the previously described hGH-N mRNAs encoding the normal 22-K growth hormone, the 20-K variant as well as a transcript lacking the third exon were found in pituitary tissue and pituitary tissue and in transiently transfected human 293-S cells. In addition, splicing products lacking either exons 3 and 4 exons 2,3 and 4 were found in both tissues. In accordance to previously reported data, the hGH-V, the hCS-A and the hCS-B genes which are expressed in placental tissue give rise to the 22-K mRNA but not to 20-K mRNA. Furthermore, no hCS mRNA arising from skipping of exon 3 was present, whereas mRNAs arising from ligation of exon 2 to exon 5 and of exon 1 to exon 5 were clearly detectable. The various hGH cDNas were expressed in vivo and screened for lactogenic activity. Only the 22-K and the 20-K variant were active in this assay. All of the hGH-N-derived differentially processed RNAs were found in cell lines of lymphoid (Hut-78) and of myelomonocytic type (U937), which had been recently described to secrete growth hormone. Interestingly, RT-PCR analysis allowed the determination of hGH-N transcripts in dermal fibroblasts. This finding underlines the importance of growth hormone in influencing immune system development and further suggests possible autocrine/paracrine regulatory loops in skin tissue.

Alternative Splicing↗
PubMed1995

[Scarring psoriatic alopecia].

Temporary hair loss is well accepted as a possible result of psoriatic plaques. On the other hand, it is still a controversial issue whether psoriasis can cause scarring alopecia. The following report presents a 38-year-old woman who had been suffering from progressive hair loss from chronic psoriatic plaques of the scalp for some years. Clinical examination revealed an area of scarring alopecia in association with typical features of psoriasis. Histology showed a cord-like fibrosis replacing former hair follicles, a perivascular lymphohistiocytic infiltrate in the upper dermis occasionally invading the follicular epithelium, and characteristic features of psoriasis of the scalp. The clinical course and the lack of evidence for any other causes of scarring alopecia suggest an aetiopathogenetic link between psoriasis and scarring alopecia. Knowledge of this relationship appears to be of practical significance, since efficient antipsoriatic therapy can stop hair loss and thus may be able to prevent scarring.

Adult↗
PubMed1995

[Generalized granuloma annulare or diffuse dermal histiocytosis?].

Generalized granuloma annulare is a rare variant of granuloma annulare affecting the trunk and extremities with a multitude of lesions. In contrast to localized granuloma annulare, generalized granuloma annulare occurs in older patients, shows a stronger association with diabetes, and is characteristically chronic. Like our 55-year-old patient, most patients present with papules and annular plaques; less often, macular or non-annular lesions may be encountered. Histology often fails to show necrobiotic or necrotic connective tissue changes demarcated by a palisading granuloma. Instead, there are diffuse dermal, band-like or nodular aggregations of histiocytes intermingled with some multinucleated giant cells and a predominantly lymphocytic infiltrate in the periphery. Because of its special characteristics, it has been suggested that generalized granuloma annulare might constitute a separate disease entity and that it should be classed among the primary cutaneous histiocytoses as a diffuse dermal histiocytosis. Using immunohistochemistry to determine the macrophage phenotype of the lesional histiocytes, we have shown that generalized granuloma annulare is not a cutaneous histiocytosis. Neither MS-1 high-molecular-weight protein, a new specific marker for cutaneous non-Langerhans cell histiocytoses, nor CD1a, the well-known marker for Langerhans cells and Langerhans cell histiocytoses, is expressed by the lesional histiocytes of our patient. In contrast, the antigen expression pattern was diagnostic for non-infectious granulomas and was highly similar to that in localized granuloma annulare. In contrast to the successful treatment of localized granuloma annulare reported with intralesional interferon beta-1, systemic treatment with interferon alpha-2b (9 x 10(6) units three times a week) was ineffective.

Biopsy↗
PubMed1995

Successful treatment of generalized lichen planus with recombinant interferon alfa-2b.

Three patients with generalized lichen planus were treated with interferon alfa-2b. The therapy was tolerated well by all patients with only minor side effects. A response was observed within 2 to 3 weeks. Itching and erythema decreased first, followed by gradual flattening and disappearance of papules and plaques after 8 to 10 weeks of treatment. After 12 weeks, therapy was discontinued after stepwise dosage reduction. In two patients, minor lesions recurred during dosage reduction. Both flares were controlled by readministration of interferon.

Adult↗
PubMed1995

Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells.

Irradiation with ultraviolet (UV) B radiation results in the formation of apoptotic keratinocytes called sunburn cells. Recently, it was demonstrated that keratinocytes can release tumor necrosis factor-alpha (TNF-alpha), which is known to cause apoptosis in particular cells. In addition, it has been shown that UVB light induces the release of TNF-alpha by keratinocytes and that keratinocytes express the 55-kD receptor for TNF-alpha. Therefore, we investigated whether TNF-alpha is involved in UV-induced apoptosis of keratinocytes. Normal human keratinocytes and HaCaT cells were exposed to UVB light, and apoptosis was examined by nick translation evaluated by fluorescence-activated cell sorter analysis. UVB induced apoptosis in a dose-dependent manner, which was confirmed by electron microscopy. Addition of a polyclonal antibody directed against human TNF-alpha immediately after UVB exposure was able to reduce DNA fragmentation. However, it was not possible to rescue all cells from apoptosis. To prove whether TNF-alpha is also involved in vivo in UVB-induced apoptosis of keratinocytes, Balb/c mice were exposed to UVB on their abdomens, skin biopsies were performed 24 h later, and sunburn cells were counted. A single dose of 2000 J/m2 caused a significant induction of sunburn cells. Subcutaneous injection of a polyclonal antibody directed against murine TNF-alpha immediately after UVB treatment resulted in a significant but incomplete reduction of sunburn cells, whereas injection of a rabbit IgG as a control had no effect. In both the in vitro and in vivo systems, application of recombinant TNF-alpha alone either to untreated keratinocytes or into normal murine skin did not induce sunburn cells. Thus, these data demonstrate that TNF-alpha is involved in UVB-induced apoptosis, but by itself is not able to induce sunburn cells. This further supports the notion that UVB-induced apoptosis of keratinocytes is a multifactorial event.

Animals↗
PubMed1995

Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins.

We report a 55-year-old man with severe inflammatory epidermolysis bullosa acquisita. The skin lesions did not respond to various immunosuppressive treatments. The combined administration of prednisone, azathioprine, dapsone and colchicine resulted only in a transient and incomplete resolution of the lesions. The bullae and increased skin fragility were successfully controlled by the addition of high-dose intravenous immunoglobulin therapy.

Azathioprine↗
PubMed1995

Treatment of urticaria pigmentosa using interferon alpha.

Long-term treatment with interferon alpha (IFN-alpha) has recently been shown to reduce the bone marrow infiltrate and cutaneous lesions in systemic mast cell disease. We therefore administered this cytokine to six patients with urticaria pigmentosa for up to 12 months, using subcutaneous injections of 5 x 10(6) U, initially five times, and subsequently three times a week. The generally well-tolerated therapy resulted in marked improvement of the cutaneous symptoms, especially in three of the patients who suffered from very severe pruritus. Two of the patients with bone marrow infiltration showed normal findings after treatment. However, in none of the patients was there any change in the skin lesions, or decrease in the degree of cutaneous mast cell infiltration, as evidenced by light and electron microscopic examination. These findings indicate that IFN-alpha is highly effective in the control of symptoms, but otherwise does not influence the cutaneous lesions of urticaria pigmentosa.

Adult↗
PubMed1995

Proto-oncogenes and oncogenes in epidermal neoplasia.

This review briefly will focus on the role of selected proto-oncogenes and their activated forms during the regulation of cell proliferation, cell death and tumor formation in the epidermis. In addition, the multiple and complex functions of these proteins in normal as well as transformed cells will be discussed.

Animals↗
PubMed1995

Cytokine treatment of mast-cell-mediated skin diseases.

Cytokines released by mast cells as well as their effects on mast cell functions appear to be of major importance in the pathogenesis of mast cell mediated skin diseases. In addition, the identification of some key mediators which were found to play a crucial in vivo rôle in certain disease states may allow the development of new therapeutic strategies using cytokines or cytokine antagonists for the treatment of inflammatory skin diseases. So far, encouraging results have been obtained when diseases with mast cell involvement such as atopic eczema or mastocytosis have been treated with different IFNs. Future trials using IFNs and other newly detected cytokines or their antagonists are required to establish effective therapy regimens.

Cytokines↗
PubMed1995

Eosinophilic pustular folliculitis: successful treatment with interferon-alpha.

Eosinophilic pustular folliculitis (Ofuji's disease) is a rare skin disease of unknown etiology characterized by infiltrated circinate plaques with sterile follicular pustules in primarily seborrheic areas. Several therapeutic regimens have been reported to control the disease with inconsistent results. We here report on a patient with Ofuji's disease, who was successfully treated with interferon-alpha 2b.

Adolescent↗
PubMed1995

Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release.

To elucidate cellular concepts for protection against ultraviolet (UV) light we investigated the effect of heat shock protein 70 (hsp70) overexpression on cell viability and on the secretion of UV-inducible immunological cytokines. Transfected murine fibrosarcoma cells (WEHI-S), overexpressing hsp70 or a sham transfected control were used. Overexpression of hsp70 was sufficient to markedly increase cell viability upon treatment with UVB (290-320 nm). Since long wave UV (UVA, 320-400 nm) as well as UVB turned out to stimulate the release of O2- radicals we studied the cell viability upon oxidative stress. Hsp70 overexpression increased viability upon treatment with hydrogen peroxide or menadione, but had no influence on UV-induced O2- release. UV-light is known to upregulate immunologic and proinflammatory cytokines such as IL-1 and IL-6. Oxidative stress appeared to exert a similar effect. Hsp70 overexpression markedly decreased the release of IL-6 induced by UVA, UVB and oxidative stress. To test whether the hsp70 mediated suppression is confined to events caused by UV-light we determined IL-1-mediated effects. IL-1-induced IL-6 release was reduced by hsp70 overexpression, whereas the IL-1 mediated activation of nuclear factor kappa B was not affected. Our data suggests that hsp70 plays a central role not only in cell protection against UV-light, but also in the regulation of proinflammatory cytokine release induced by UV-exposure.

Animals↗
PubMed1994

IL-12 is expressed and released by human keratinocytes and epidermoid carcinoma cell lines.

IL-12 is a 70-kDa heterodimeric cytokine composed of two covalently linked chains, p40 and p35. IL-12 has multiple effects on T and NK cells and recently was found to be required for optimal Th1 cell development. In a variety of inflammatory skin disorders including delayed type hypersensitivity and contact hypersensitivity, Th1 cells appear to be critically involved. Because keratinocytes are well known to exhibit the capacity to release a variety of proinflammatory and immunologic cytokines, and thereby to be able to modulate inflammatory and immune reactions within the skin, it was investigated whether human keratinocytes and keratinocyte cell lines can release IL-12. Supernatants of phorbol-12,13-dibutyrate (PDBu) stimulated human epidermoid carcinoma cell lines (KB, A431) induced IFN-gamma production by PBL. This activity could be completely blocked by the addition of an anti-IL-12 Ab directed against the p40 subunit of IL-12 (C8.6). Release of IL-12 by keratinocyte cell lines was further confirmed by an RIA specific for p40. Immunoprecipitation under reducing conditions using the C8.6 Ab yielded specific bands at 40 kDa in supernatants of both KB cells and normal human keratinocytes. Northern blot analysis revealed IL-12-specific mRNA transcripts in PDBu-treated KB cells using cDNA probes encoding for p35 and p40. Moreover, by reverse transcription PCR specific transcripts for p35 and p40 were found in keratinocytes. These data indicate that keratinocyte cell lines and, although to a much lesser degree, normal human keratinocytes, exhibit the capacity to make IL-12; thus demonstrating for the first time IL-12 production by nonhemopoietic cells. Thus, one may speculate that keratinocytes via this capacity may influence the fate of Th-mediated immune responses, favoring Th1 responses by enhanced production of IL-12 or Th2 responses by reduced IL-12 release.

Base Sequence↗
PubMed1994

Increased tumorigenicity of human keratinocytes harboring human papillomavirus type 16 is associated with resistance to endogenous tumor necrosis factor-alpha-mediated growth limitation.

The aim of this study was to evaluate the relationship between tumorigenicity of cell sublines derived from weakly tumorigenic SKv-e and SKv-l keratinocytes harboring human papillomavirus type 16 (HPV16) and their susceptibility to autocrine growth limitation mediated by tumor necrosis factor-alpha (TNF-alpha). These sublines displayed different in vitro proliferative potential which correlated with tumorigenicity in nu/nu mice. Recombinant TNF-alpha inhibited in vitro growth of weakly tumorigenic parental SKv cell lines while it did not affect proliferation of their respective highly tumorigenic sublines. Resistance to TNF-alpha correlated with both increased in vitro proliferation and tumorigenicity. Anti-TNF-alpha antibodies (Ab) significantly increased in vitro proliferation of weakly tumorigenic parental SKv cells up to the levels of their highly tumorigenic sublines. Growth of highly tumorigenic SKv cells was not affected. On the other hand, proliferation of SKv cells was affected neither by transforming growth factor-beta (TGF-beta) nor by anti-TGF-beta Ab. All SKv cell sublines tested spontaneously released TNF-alpha, as evaluated by a specific radioimmunoassay; however, the levels of the endogenous cytokine were not related to their proliferative potential and tumorigenicity. An increased resistance to the anti-proliferative effect of TNF-alpha may be associated with decreased expression of TNF-alpha receptors (TNF-alpha R) inasmuch as evaluation of 125I-TNF-alpha binding and Northern-blot analysis of TNF-alpha R-specific mRNA showed that highly tumorigenic SKv cell sublines expressed significantly lower numbers of TNF-alpha R than their respective parental cells. These results show that an increased tumorigenicity of HPV16-harboring SKv keratinocytes may be, at least partially, due to escape from autocrine TNF-alpha-mediated growth limitation.

Animals↗
PubMed1994

Proopiomelanocortin production by epidermal cells: evidence for an immune neuroendocrine network in the epidermis.

Proopiomelanocortin (POMC) is known to be synthesized in the pituitary gland and is subsequently cleaved by specific prohormone convertases into biologically active peptide hormones such as melanocyte stimulating hormones (MSH), adrenocorticotropin (ACTH) and endorphins (EP). Guanine nucleotide-binding protein (G-protein)-coupled receptors, which have only recently been discovered, are involved in the transmission of their message. There is also evidence indicating that POMC is not only produced by pituitary cells but is an ubiquitous molecule, that is cleaved cell- and tissue-specific. It has also been shown that the epidermis keratinocytes as well as melanocytes express POMC upon stimulation and release alpha MSH and ACTH. In addition to their function as hormones, POMC peptides have been shown to exert a variety of immunoregulatory effects by modulating the function of immunocompetent cells as well as cytokines. These findings provide further evidence for the immunoneuroendocrine network playing a crucial role during the pathogenesis of immune and inflammatory skin disease.

Animals↗
PubMed1994

UVB light induces nuclear factor kappa B (NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts.

It has been shown previously that ultraviolet (UV) light (290-320 nm) activates keratinocytes to release proinflammatory cytokines including interleukin (IL)-6. Because the 5' flanking region of the IL-6 gene contains a consensus NF kappa B binding sequence, the effect of UVB light on an NF kappa B-like binding activity was investigated in a human epidermoid carcinoma cell line (A431). Nuclear factor kappa B (NF kappa B) activation in the cytoplasm is known to be due to the dissociation of an inactive NF kappa B-inhibitor of nuclear factor kappa B (I kappa B) complex. Cytosolic extracts from cells harvested shortly after sublethal UVB irradiation showed a UVB dose-dependent increase of NF kappa B binding. The activation was reduced by radical scavenging chemicals, suggesting involvement of reactive oxygen intermediates. NF kappa B activation has been shown previously to be triggered by DNA lesions induced by UV light. To elucidate whether DNA damage is necessary and sufficient to mediate NF kappa B activation crude, cytosolic protein extracts obtained from unirradiated cells were exposed to UVB light. This in vitro UVB treatment led to activation of an NF kappa B-like binding activity, suggesting an additional signaling pathway independent of chromosomal DNA damage or byproducts of DNA damage. The activation process was dependent on the presence of membranes. The data suggest at least an additional signaling pathway for the early UVB response, including a component of the pathway residing at the cell membrane.

Antioxidants↗