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Markus Böhm

Publications and source records attributed to Markus Böhm.

At least 19 recordsLinked to original sources
PubMed2006

Regulation of constitutive and UVR-induced skin pigmentation by melanocortin 1 receptor isoforms.

Melanin synthesized by epidermal melanocytes protects the skin against UVR-induced DNA damage and skin cancer. Exposure to UVR increases the synthesis of the photoprotective eumelanin on activation of MC1R, a melanoma susceptibility gene. We studied the expression of MC1R under UVR and alpha-MSH stimulation in skin of different ethnic origins and in melanocytes of various pigmentary levels. This study identifies and characterizes a novel MC1R isoform (MC1R350) generated by alternative splicing of the classically known MC1R (MC1R317). We demonstrate that the melanin content of melanocytes shows a significant positive correlation with MC1R317 levels but correlates inversely with the amount of MC1R350, suggesting that this latter isoform could act as a negative regulator of melanin synthesis. We confirmed that hypothesis by showing that while MC1R317 signaling significantly increases the expression of MITF and tyrosinase, two key factors in the melanin synthesis pathway, MC1R350 dramatically hampers their expression. In the skin, we show that UVR does not increase MC1R350 expression but does significantly increase MC1R317. Taken together, our results strongly suggest that MC1R350 acts as a negative regulator of skin pigmentation and demonstrate for the first time that MC1R isoform-specific expression is closely related to skin pigmentation and photoprotection.

Alternative Splicing↗
PubMed2006

Human mast cells in the neurohormonal network: expression of POMC, detection of precursor proteases, and evidence for IgE-dependent secretion of alpha-MSH.

Human mast cells have been shown to release histamine in response to the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH), but it is unknown whether these cells express proopiomelanocortin (POMC) or POMC-derived peptides. We therefore examined highly purified human skin mast cells and a leukemic mast cell line-1 (HMC-1) for their ability to express POMC and members of the prohormone convertase (PC) family known to process POMC. Furthermore, we investigated whether these cells store and secrete alpha-MSH. Reverse transcriptase-PCR (RT-PCR) analysis revealed that both skin mast cells and HMC-1 cells express POMC mRNA and protein. Expression of the POMC gene at the RNA level in HMC-1 cells could be confirmed by Northern blotting. Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR. In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells. Radioimmunoassays performed on cell lysates and cell culture supernatants from human skin-derived mast cells disclosed immunoreactive amounts of alpha-MSH in both fractions. Stimulation with an anti-IgE antibody significantly reduced intracellular alpha-MSH and increased extracellular levels, indicating IgE-mediated secretion of this neuropeptide. Our findings show that human mast cells are active players in the cutaneous POMC system. Mast cell-derived alpha-MSH may contribute to cutaneous hyperpigmentation as seen in patients with urticaria pigmentosa. Moreover, IgE-dependent release of alpha-MSH suggests an immunomodulatory role of this neurohormone during inflammatory and allergic reactions of the skin.

Cell Line, Tumor↗
PubMed2006

A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus.

OBJECTIVE: To investigate the safety and efficacy of oral methylprednisolone combined with azathioprine sodium or mycophenolate mofetil for the treatment of pemphigus. DESIGN: A prospective, multicenter, randomized, nonblinded clinical trial to compare 2 parallel groups of patients with pemphigus (pemphigus vulgaris and pemphigus foliaceus) treated with oral methylprednisolone plus azathioprine or oral methylprednisolone plus mycophenolate mofetil. Settings Thirteen departments of dermatology in Germany. Patients We included patients with pemphigus vulgaris (n = 33) or pemphigus foliaceus (n = 7) evidenced by clinical lesions suggestive of pemphigus, intraepidermal blistering on histological analysis of skin biopsy specimens, intercellular deposition of IgG within the epidermis, and immunoblot analysis findings for antidesmoglein 3 and/or antidesmoglein 1 autoantibodies. MAIN OUTCOME MEASURES: The cumulative total methylprednisolone doses and rate of remission. Secondary outcome measures were safety profiles and duration of remission. RESULTS: In 13 (72%) of 18 patients with pemphigus receiving oral methylprednisolone and azathioprine, complete remission was achieved after a mean +/- SD of 74 +/- 127 days compared with 20 (95%) of 21 patients receiving oral methylprednisolone and mycophenolate mofetil in whom complete remission occurred after a mean +/- SD of 91 +/- 113 days. The total median cumulative methylprednisolone dose used was 8916 mg (SD, +/-29 844 mg) in the azathioprine group compared with 9334 mg (SD, +/-13 280 mg) in the mycophenolate group. In 6 (33%) of 18 patients treated with azathioprine, grade 3 or 4 adverse effects were documented in contrast to 4 (19%) of 21 patients who received mycophenolate mofetil. Conclusion Mycophenolate mofetil and azathioprine demonstrate similar efficacy, corticosteroid-sparing effects, and safety profiles as adjuvants during treatment of pemphigus vulgaris and pemphigus foliaceus.

Administration, Oral↗
PubMed2006

Dermatomyositis associated with malignant melanoma--a marker of poor prognosis?

BACKGROUND: Dermatomyositis (DM) is an inflammatory connective tissue disorder well recognized as a paraneoplastic syndrome in adults. OBJECTIVE: The objective of this study was to assess the prognosis of DM associated with malignant melanoma (MM). PATIENTS AND METHODS: We systematically searched databases (PubMed, MEDLINE, and WEB OF SCIENCE) for articles reporting the concurrence of DM and MM. For the literature study, time of onset of DM in relation to diagnosis of MM (before, concomitant with, or after), stage of MM after restaging (according to the American Joint Committee on Cancer [AJCC] guidelines, 2001), and survival time after diagnosis of DM were recorded. Survival time studies and univariate statistical analyses were performed. Furthermore, we present our own clinical case of a patient with DM concomitantly occurring with regional lymph node metastasis of MM. RESULTS: In 5 cases DM occurred before, in 6 cases concomitantly with, and in 6 cases after progression of MM. Univariate analysis identified the AJCC stage of MM as a significant prognostic factor. Gender, age, and the time interval between onset of DM and progression of melanoma were unrelated. The 1-year actuarial survival rate was 0% for patients with DM when occurring with MM at stage IV and 60% when occurring with MM at stage III (P < .05). The estimated mean survival time was 6.6 months for patients with MM stage IV and 57 months for stage III. LIMITATIONS: The conclusions from this study are limited by the relatively small number of articles that reported the association of MM and DM. CONCLUSION: DM occurring in patients with MM at stage IV is connected with an extremely poor prognosis, whereas the few reported patients with DM and MM at stage III, including our case, have a prognosis similar to stage III patients without DM.

Adult↗
PubMed2006

Melanocortin receptor ligands: new horizons for skin biology and clinical dermatology.

The melanocortin (MC) system is probably the best characterized neuropeptide network of the skin. Most cutaneous cell types express MC receptors (MC-Rs) and synthesize MCs, such as alpha-melanocyte-stimulating hormone (alpha-MSH), that act in autocrine and paracrine fashion. In human skin cells, activation of adenylate cyclase by MCs occurs at 10(-6)-10(-9) M doses of the ligand, but effects are induced in some cell types at subnanomolar concentrations. In addition to the pigmentary action of MCs on epidermal melanocytes, the hair follicle is a source and target for MCs. MCs regulate lipogenesis in sebocytes expressing both MC-1R and MC-5R. In adipocytes, lipid metabolism is modulated by agouti signalling protein, a natural MC-1R/MC-4R antagonist. The anti-inflammatory activity of alpha-MSH includes immunomodulatory effects on several resident skin cells and antifibrogenic effects mediated via MC-1R expressed by dermal fibroblasts. In human mast cells, alpha-MSH appears to be proinflammatory due to histamine release. alpha-MSH exhibits cytoprotective activity against UVB-induced apoptosis and DNA damage, a finding that helps explain the increased risk of cutaneous melanoma in individuals with loss of function MC-1R mutations. These findings should improve our understanding of skin physiology and pathophysiology and may offer novel strategies with MCs as future therapeutics for skin diseases.

Animals↗
PubMed2005

Improving binding mode predictions by docking into protein-specifically adapted potential fields.

The development of a protein-specifically adapted objective function for docking is described. Structural and energetic information about known protein-ligand complexes is exploited to tailor knowledge-based potentials using a "reverse", protein-based CoMFA-type (=AFMoC) approach. That way, effects due to protein flexibility and information about multiple solvation schemes can be implicitly incorporated. Compared to the application of AFMoC for binding affinity predictions, a Shannon entropy based column filtering of the descriptor matrix and the capping of adapted repulsive potentials within the binding site have turned out to be crucial for the success of this method. The new developed approach (AFMoC(obj)) was validated on a data set of 66 HIV-1 protease inhibitors, for which experimental structural information was available. Convincingly, for ligands with up to 20 rotatable bonds, in more than 75% of all cases a binding mode below 2 A rmsd has been identified on the first scoring rank when AFMoC(obj)-based potentials were used as the objective function in AutoDock. With respect to nonadapted DrugScore or AutoDock fields, the binding mode prediction accuracy was significantly improved by 14%. Noteworthy, very similar results were obtained for training and test set compounds, demonstrating the strength and robustness of this method. Implications of our findings for binding affinity predictions and its usage in virtual screening are further discussed.

Binding Sites↗
PubMed2005

Detection of functionally active melanocortin receptors and evidence for an immunoregulatory activity of alpha-melanocyte-stimulating hormone in human dermal papilla cells.

Proopiomelanocortin (POMC)-derived peptides and their receptors have been identified in many peripheral organs including the skin in which they exert a diversity of biological actions. We investigated the expression and potential role of the POMC system in human dermal papilla cells (DPCs), a specialized cutaneous mesenchymal cell type regulating hair follicle activity. In culture, these cells expressed POMC and displayed immunoreactivity for ACTH, alphaMSH, and beta-endorphin. Among the prohormone convertases (PCs) tested, only PC2, its chaperone 7B2, and furin convertase but not PC1 and paired basic amino acid cleaving enzyme 4 gene were detected. Human DPCs in vitro expressed both the melanocortin-1 receptor (MC-1R) and MC-4R, and immunoreactivity for these receptors was also present in cells of the human dermal papilla in situ. In contrast to the dermal papilla of agouti mice, agouti signaling protein, a natural and highly selective MC-1R and MC-4R antagonist, was undetectable in human DPCs. The MC-Rs detected in human DPCs were functionally active because alphaMSH increased intracellular cAMP and calcium. Preincubation of the cells with a synthetic peptide corresponding to the C-terminal domain of agouti signaling protein abrogated cAMP induction by alphaMSH. Furthermore, alphaMSH was capable of antagonizing the expression of intercellular adhesion molecule-1 induced by the proinflammatory cytokine interferon-gamma. Our data suggest a regulatory function of alphaMSH within the dermal papilla whose disruption may lead to deregulation of immune and inflammatory responses of the hair follicle, thereby possibly contributing to the development of inflammatory forms of alopecia.

Adrenocorticotropic Hormone↗
PubMed2004

alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage.

Ultraviolet radiation is a well established epidemiologic risk factor for malignant melanoma. This observation has been linked to the relative resistance of normal melanocytes to ultraviolet B (UVB) radiation-induced apoptosis, which consequently leads to accumulation of UVB radiation-induced DNA lesions in melanocytes. Therefore, identification of physiologic factors regulating UVB radiation-induced apoptosis and DNA damage of melanocytes is of utmost biological importance. We show that the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) blocks UVB radiation-induced apoptosis of normal human melanocytes in vitro. The anti-apoptotic activity of alpha-MSH is not mediated by filtering or by induction of melanin synthesis in melanocytes. alpha-MSH neither leads to changes in the cell cycle distribution nor induces alterations in the expression of the apoptosis-related proteins Bcl(2), Bcl(x), Bax, p53, CD95 (Fas/APO-1), and CD95L (FasL). In contrast, alpha-MSH markedly reduces the formation of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers, ultimately leading to reduced apoptosis. The reduction of UV radiation-induced DNA damage by alpha-MSH appears to be related to induction of nucleotide excision repair, because UV radiation-mediated apoptosis was not blocked by alpha-MSH in nucleotide excision repair-deficient fibroblasts. These data, for the first time, demonstrate regulation of UVB radiation-induced apoptosis of human melanocytes by a neuropeptide that is physiologically expressed within the epidermis. Apart from its ability to induce photoprotective melanin synthesis, alpha-MSH appears to exert the capacity to reduce UV radiation-induced DNA damage and, thus, may act as a potent protection factor against the harmful effects of UV radiation on the genomic stability of epidermal cells.

Apoptosis↗
PubMed2004

Non-thiol farnesyltransferase inhibitors: utilization of the near aryl binding site by 5-arylacetylaminobenzophenones.

We recently described two novel aryl binding sites of farnesyltransferase. The arylacetyl residue was designed as an appropriate substituent for our benzo-phenone-based AAX-peptidomimetic compound capable of occupying the near aryl binding site which is located next to the catalytic zinc ion. Non-thiol farnesyl-transferase inhibitors with micromolar to submicromolar activity were obtained.

Alkyl and Aryl Transferases↗
PubMed2004

Solar-simulated ultraviolet radiation-induced upregulation of the melanocortin-1 receptor, proopiomelanocortin, and alpha-melanocyte-stimulating hormone in human epidermis in vivo.

Ultraviolet light is one of the most crucial environmental factors with regard to its capacity to induce skin cancer, premature aging of the skin, and immunosuppression. Although ultraviolet directly affects the function of epidermal cells, many of these effects are mediated by induction of cytokines, growth factors, and neuropeptides, such as alpha-melanocyte-stimulating hormone. Recently, in addition to its well-known pigmentation inducing activity, a strong anti-inflammatory as well as an immunomodulatory potential of alpha-melanocyte-stimulating hormone has been recognized. The aim of this study was to determine, whether ultraviolet irradiation affects the expression of both alpha-melanocyte-stimulating hormone and the melanocortin-1 receptor in human epidermis in vivo. The volar aspects of the forearms were exposed to twice the minimal erythema dose of solar-simulating radiation. Three, 6, and 24 h after irradiation, the proopiomelanocortin and interleukin-10 mRNA levels in suction blister induced epidermal sheets were considerably upregulated as detected by semiquantitative reverse transcription-polymerase chain reaction. Furthermore, alpha-melanocyte-stimulating hormone and interleukin-10 protein levels in blister fluids were significantly increased 24 h after ultraviolet irradiation, an effect that could be abolished by application of the broad-spectrum sunscreen Anthélios XL prior to ultraviolet (solar-simulating radiation) exposure. In addition, enhanced melanocortin-1 receptor mRNA and receptor protein expression upon solar-simulating radiation was ascertained by reverse transcription-polymerase chain reaction and immunohistochemistry of the epidermal sheets, respectively. Proopiomelanocortin-derived neuropeptides, such as alpha-melanocyte-stimulating hormone may therefore play an important part in modulating ultraviolet-induced inflammation.

Adolescent↗
PubMed2004

Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma.

Cytokine resistance is a well-established feature of melanoma cell progression and represents also a major obstacle in immunotherapy of patients with metastatic melanoma. To check whether suppressors of cytokine signalling (SOCS) play a role in cytokine resistance and tumor progression of melanoma, we investigated the expression and regulation of SOCS-1, an established negative regulator of interleukin-6 (IL-6) and interferon (IFN) signalling. In vitro SOCS-1 transcripts were detectable by RT-PCR in 8 out of 8 human melanoma cell lines derived from different tumor stages. Normal human melanocytes also expressed SOCS-1 mRNA in the presence or absence of artificial growth factors. Both IL-6 and alpha-IFN induced rapid and transient SOCS-1 mRNA expression in WM35 and WM9 melanoma cells. At the protein level, SOCS-1 was undetectable in normal human melanocytes whereas uniformly expressed in all tested melanoma cell lines. The aberrant SOCS-1 protein expression in melanoma cells was recapitalized in situ as shown by immunohistochemical analysis. SOCS-1 immunoreactivity was closely related to tumor invasion (Clark level), tumor thickness according to Breslow, and stage of the disease. In contrast, melanocytes in normal skin or melanocytic nevi lacked SOCS-1 protein expression. Our findings show that melanoma cells express a member of the SOCS family, SOCS-1, in vitro and in situ. SOCS-1 is a progression marker of human melanoma and may downregulate biological responses by endogenous and/or therapeutically administered cytokines.

Antineoplastic Agents↗
PubMed2004

Neuroendocrine regulation of sebocytes -- a pathogenetic link between stress and acne.

A causative link between emotional stress and acne has long been postulated. There is mounting evidence that the molecular mechanism underlying this observation is related to the expression of receptors for several neuroendocrine mediators by the sebaceous gland. Recent and ongoing studies have indicated that human sebocytes express functional receptors for corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y and calcitonin gene-related peptide. After ligand binding, these receptors modulate the production of inflammatory cytokines, proliferation, differentiation, lipogenesis and androgen metabolism in sebocytes. By means of their autocrine, paracrine and endocrine actions, these neuroendocrine factors appear to mediate centrally and topically induced stress towards the sebaceous gland, ultimately affecting the clinical course of acne.

Acne Vulgaris↗
PubMed2004

Melanocortins in fibroblast biology--current update and future perspective for dermatology.

The skin is a target organ and source for proopiomelanocortin (POMC)-derived peptides, such as alpha-melanocyte-stimulating hormone (alpha-MSH), which acts by binding to melanocortin receptors (MC-Rs). Recent progress in our understanding of the cutaneous POMC system has demonstrated that human dermal fibroblasts (HDFs) are a novel target for alpha-MSH. MC-1R is expressed by HDFs in vitro and in situ. MC-1R expression is also detectable in human connective tissue sheath fibroblasts (CTSFs) and in dermal papilla cells (DPCs) of the hair follicle, the latter concomitantly expressing MC-1R and MC-4R in vitro and in situ. Both HDFs and DPCs are capable of generating POMC-derived peptides, although cell-specific differences exist in the expression of prohormone convertases and the amounts of POMC-derived peptides generated. Functional studies have shown that alpha-MSH exerts anti-inflammatory actions in human fibroblastic skin cells by suppressing interleukin-1 (IL-1)-induced IL-8 production, activation of the transcription factor activator protein-1 (AP-1) and induction of intercellular adhesion molecule-1 by interferon-alpha. In addition, alpha-MSH antagonizes the effect of transforming growth factor-beta1 (TGF-beta1) on collagen synthesis in HDFs in vitro and exerts antifibrogenic activity in a mouse model of cutaneous fibrosis. These findings indicate that fibroblastic cells participate in the cutaneous POMC system in which alpha-MSH appears to act as a modulator of inflammatory and fibrogenic responses. The biological activities of alpha-MSH in fibroblastic cells of the skin point towards novel clues in our understanding of the pathophysiology of fibrotic skin disorders and inflammatory diseases of the hair follicle and, finally, suggest innovative therapeutic options for the treatment of these conditions.

Animals↗
PubMed2003

Collagen metabolism is a novel target of the neuropeptide alpha-melanocyte-stimulating hormone.

Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that alpha-melanocyte-stimulating hormone (alpha-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. Alpha-MSH in vitro suppresses the synthesis of collagen types I, III, and V and down-regulates the secretion of procollagen type I C-terminal peptide (PICP) in human dermal fibroblasts treated with the fibrogenic cytokine transforming growth factor-beta1 (TGF-beta1). Alpha-MSH did not interfere with TGF-beta1 signaling, because TGF-beta1-induced expression of collagen mRNA was not affected, implying a posttranscriptional mechanism. Human dermal fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R). Immunohistochemical studies on normal adult human skin confirmed MC-1R expression in distinct dermal fibroblastic cells. The MC-1R on fibroblasts appears to be functionally relevant because alpha-MSH increased the amount of intracellular cAMP, and coincubation with a synthetic peptide corresponding to the human Agouti signaling protein abrogated the inhibition of TGF-beta1-induced PICP secretion by alpha-MSH. To assess the in vivo relevance of these findings, a mouse model was used in which dermal fibrosis was induced by repetitive intracutaneous injections with TGF-beta1. The inductive activity of TGF-beta1 on collagen deposition and the number of dermal cells immunoreactive for vimentin and alpha-smooth muscle actin was significantly suppressed by injection of alpha-MSH. Melanocortins such as alpha-MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders.

Actins↗
PubMed2003

Successful treatment of anogenital lichen sclerosus with topical tacrolimus.

BACKGROUND: Lichen sclerosus of the anogenital area is a chronic inflammatory and fibrosclerotic disease associated with substantial morbidity. Topical ultrapotent corticosteroids are currently the treatment of choice. OBSERVATIONS: Three prepubertal girls and 3 adults (2 men, 1 woman) were treated with 0.1% tacrolimus ointment once daily. All patients experienced complete resolution with long-lasting remission for up to 1 year. No major adverse effects were observed, and treatment was well tolerated. CONCLUSIONS: Topical tacrolimus is a promising novel agent in the treatment of lichen sclerosus of the anogenital area. A major advantage over topical corticosteroids is the lack of skin atrophy. Further clinical trials are warranted to confirm our findings.

Administration, Topical↗