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  • 1
    Electronic Resource
    Electronic Resource
    Processing of POMC peptides by dermal microvascular endo-thelial cells: implication for EC biologic functions and skin inflammation (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc.
    Experimental dermatology 13 (2004), S. 0 
    Details
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Dermal microvascular endothelial cells (ECs) are both source and target of the pro-opiomelanocortin (POMC) peptides ACTH and α-melanocyte-stimulating hormone (α-MSH). The availability of neuropeptides as important modulators of innate and adaptive immune responses is controlled by neuropeptide-specific peptidases such as neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE). In this study, we have tested the possibility that NEP or ACE expressed by ECs may influence the local bioavailability of POMC peptides. Incubation of ACTH1−39 with cell membranes prepared from the high NEP-/low ACE-expressing microvascular EC line 1 (HMEC-1) or from low NEP-/high ACE-expressing primary human dermal ECs (HDMECs) for 30–480 min resulted in a decrease in ACTH immunoreactivity (IR) over time in membrane supernatants that could be partially blocked with NEP inhibitors as detected by radioimmunoassay. In parallel, α-MSH IR increased peaking after 60 min. Fragments generated by incubation of HMEC-1 or HDMEC membranes with ACTH1−39, ACHT1−24 or α-MSH for 1–120 min were further analysed by mass spectroscopy. HMEC-1 membranes generated peptide products which could be altered by inhibition of NEP, but not ACE. Likewise, HDMEC membranes fragmented ACTH similar to HMEC-1 membranes in the presence of NEP inhibitors. Some of the proteins can be assigned to regular proteolytic cleavage, while others seem to be modified. Importantly, HMEC-1 and HDMEC membranes also slowly degraded α-MSH, suggesting that EC proteolytic peptidases locally control ACTH/α-MSH bioavailability, which may be important in controlling cutaneous inflammation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0906-6705.2004.0212cc.x
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  • 2
    Electronic Resource
    Electronic Resource
    α-MSH and fragments: potential therapeutic agents in inflammation (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc
    Experimental dermatology 13 (2004), S. 0 
    Details
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: α-Melanocyte-stimulating hormone (α-MSH) exerts numerous immunomodulatory and anti-inflammatory activities, which at least partly are mediated through the melanocortin receptor-1 (MC-1R), expressed on monocytes, dermal fibroblasts, dendritic cells (DCs), endothelial, and epithelial cells. Accordingly, α-MSH downregulates the production of proinflammatory cytokines and the expression of costimulatory molecules on antigen-presenting cells (APCs) via inhibiting the activation of transcription factors such as NF-κB, while upregulating the production of suppressor factors such as IL-10. Besides α-MSH, its C-terminal-tripeptide KPV and the IL-1β-derived tripeptide KPT are capable of modulating APC functions. Using a mouse model of contact hypersensitivity (CHS), systemic and epicutaneous application of α-MSH, KPV, or KPT inhibited CHS induction and induced hapten-specific tolerance. However, using MC-1R-deficient mice (MC-1Re/e), tolerance induction was found to be independent of MC-1R expression. To further investigate the mechanisms responsible for tolerance induction, adoptive transfer experiments were performed. α-MSH-treated haptenized DCs inhibited CHS and induced hapten-specific tolerance, via induction of regulatory T lymphocytes (Treg). In contrast, using a murine model of intestinal inflammation [Dextransulfate (DSS)-induced colitis], the expression of a functional MC-1R was found to be crucial for α-MSH to exert its anti-inflammatory activity; in wt mice, weight loss was reduced and the survival rate significantly was improved upon treatment with α-MSH or KPV. However, DSS colitis was significantly aggravated in MC1-Re/e mice, resulting in the death of all animals. Bone marrow transplantation from wt mice did not alter the course of inflammation, indicating that MC-1R expression on non-hematopoietic cells is crucial for host defense. These findings further support the therapeutic potential of α-MSH-related peptides for the treatment of inflammatory, autoimmune, and allergic diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0906-6705.2004.0212ao.x
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  • 3
    Electronic Resource
    Electronic Resource
    Calcitonin gene-related peptide and adrenomedullin modulate cytokine-induced microvascular endothelial cell cellular adhesion molecule expression and NF-κB activation (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc
    Experimental dermatology 13 (2004), S. 0 
    Details
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: AM and the sensory neuropeptide CGRP are potent vasoactive mediators that activate high-affinity G-protein-coupled receptors consisting of receptor-activity modifying proteins (RAMPs) and a seven-transmembrane domain calcitonin receptor-like receptor (CRLR) with RAMP-1/CRLR as CGRP and RAMP2 or -3/CRLR as AM receptors. In this study, we have examined the possibility that AM or CGRP modulate dermal microvascular EC adhesion molecule (ICAM-1 and VCAM-1) expression. Primary HDMEC or cells of the EC line HMEC-1 were transfected with cDNA expression vectors for an EGFP control, RAMP-1, RAMP-2 and CRLR by electroporation, or left untransfected. Stimulation of EC-overexpressing R1/CRLR or R2/CRLR with CGRP or AM (0.01–1000 nm) resulted in a dose-dependent upregulation of intracellular cAMP. Importantly, when HDMEC transfected with R1/CRLR or R2/CRLR were treated with TNFα in combination with CGRP or AM, these peptides interfered with the TNF-induced expression of ICAM-1 and VCAM-1 as well as the adhesion of lymphoblastoid cell lines to HDMEC monolayer in a biphasic manner. Likewise, AM and CGRP modulated the activation of nuclear factor κB (NF-κB) partly by inhibiting the TNFα-induced degradation of cytosolic IκBα. Neither transfection with the orphan CRLR nor RAMPs alone was capable of mediating a full reduction of TNFα-induced ICAM-1 or VCAM-1 expression. In conclusion, CGRP and more pronounced AM are capable of modulating TNFα-induced EC CAM expression, which may be of importance for the regulation of leucocyte–endothelial cell interaction during cutaneous neurogenic inflammation.This study was supported by the “Medizinische Forschungsgesellschaft Salzburg” and a grant of the Austrian Science Foundation (P14906).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0906-6705.2004.0212bu.x
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  • 4
    Electronic Resource
    Electronic Resource
    Functional absence of neutral endopeptidase in mice promotes hapten uptake, maturation and function of bone marrow-derived dendritic cells (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc
    Experimental dermatology 13 (2004), S. 0 
    Details
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The bioavailability of neuropeptides such as substance P (SP) released from sensory nerves or immune cells during skin inflammation is effectively controlled by proteolytic peptidases. Acute inhibition or genomic deletion of neutral endopeptidase (NEP) results in a SP-dependent augmentation of murine allergic contact dermatitis (ACD) by affecting sensitization and elicitation phase. In this study, we address the hypothesis that absence of NEP may modulate ACD responses by affecting bone marrow-derived dendritic cell (BmDC) maturation and function. BmDCs were generated from NEP-deficient mice (C57BL/6J-NEP–/–) or wild-type controls (C57BL/6J). FACS analysis revealed that d3, d6 and d7 NEP–/– BmDCs expressed significantly more DC cell-surface markers and costimulatory molecules compared to NEP+/+ mice BmDCs, in particular after BmDC maturation with LPS. In MLR utilizing d8 BmDCs pulsed 3 h in vitro with DNBS and T cells from in vivo DNFB-haptenized NEP–/– and NEP+/+ mice, BmDCs from NEP–/– animals promoted proliferation of T cells with higher efficacy compared to wild-type mice BmDCs. Likewise, T cells from NEP–/– mice demonstrated a higher proliferative response to Concavalin A stimulation or CD3/CD28 ligation compared to NEP+/+ mice. In addition, acute systemic NEP inhibition in NEP+/+ mice prior to sensitization with fluorescein isothiocyanate (FITC) after 24 h significantly augmented uptake of FITC in the CD11c-positive DC fraction from regional lymph nodes but not from spleen compared to cells obtained from mice not treated with the NEP inhibitor. These data indicate that functional absence of NEP may significantly control cutaneous ACD inflammatory responses by promoting hapten uptake, DC maturation and T-cell stimulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0906-6705.2004.0212bz.x
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  • 5
    Electronic Resource
    Electronic Resource
    Neuropeptides, a never-ending story? Termination of cutaneous inflammation by proteolytic peptidases (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc
    Experimental dermatology 13 (2004), S. 0 
    Details
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neuropeptide-specific peptidases such as neutral endopeptidase (NEP, CD10) and angiotensin-converting enzyme (ACE, CD143) effectively control the bioavailability of neuropeptides released from sensory nerves, immune and skin cells during neurogenic inflammation. Drug inhibition or genomic deletion of NEP or ACE results in a substance P (SP-) and bradykinin-dependent augmentation of murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation. The functional absence of NEP enhanced ACD inflammation by promoting bone marrow-derived dendritic cell (BmDC) maturation and function. In vitro haptenized BmDCs from NEP–/– mice neurokinin-1 receptor-dependently stimulated proliferation of antigen-specific NEP–/– and NEP+/+ T cells with higher efficacy compared to NEP+/+-mice BmDCs. Importantly, adoptive transfer of in vitro haptenized DC from NEP–/– into wild-type mice significantly promoted ACD in comparison with transfer of NEP+/+DC. Likewise, hapten uptake into DC from regional lymph nodes during ACD sensitization is increased in NEP–/– mice compared to normal mice. Moreover, in CD10- and CD143-expressing human dermal microvascular endothelial cells and keratinocytes, UV light and inflammatory mediators regulated mRNA and protein expression, as well as proteolytic activity of these peptidases, which may be important for cell survival and the outcome of an inflammatory response. Likewise, NEP and ACE are also involved in the proteolytic processing of neuroendocrine hormones such as adrenocorticotropin and α-melanocyte-stimulating hormone. Thus, present data indicate that ACE and NEP by proteolytic cleavage of peptide mediators have a significant role in controlling cutaneous inflammatory responses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0906-6705.2004.00212y.x
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