Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human Langerhans cells (LC) express CD45, but clear data about the isoform(s) and their function(s) are lacking. In the present study, double labeling experiments reveal that freshly isolated LC from normal skin are CD45RO+/RA-/RB-. However, after isolation and short-time culture where LC undergo an in vitro maturation resembling that to lymphoid dendritic cells, CD45RB emerges whereas CD45RO expression decreases. This evolution results from dynamic alternative RNA splicing. Addition of granulocyte-macrophage colony-stimulating factor or tumor necrosis factor-alpha to short-time cultures has no significant effect on CD45RB, but both cytokines accelerate the loss of CD45RO. LC isolated from lesional skin of atopic eczema highly express CD45RO and CD45RB. Cross-linking of CD45 on LC isolated from atopic individuals inhibits the calcium mobilization in response to activation via Fc epsilon receptor type I (Fc epsilon RI). Hence, the protein tyrosine phosphatase CD45 from human LC is subjected to a splicing phenomenon related to the differentiation and activation stage of these cells and regulates their Fc epsilon RI-mediated activation.
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PMID:Characterization of the protein tyrosine phosphatase CD45 on human epidermal Langerhans cells. 787 93

In the dermal sites of atopic skin, eosinophil (Eo) granule protein or more rarely intact Eos represent a characteristic histological feature. We addressed the question of whether lesional scales of patients with various eosinophilic skin disorders contain Eo attractant and tried to characterize it biochemically. In scales of a patient with drug reaction, heparin-binding Eo attractants could be identified. High-performance liquid chromatographic analyses together with specific ELISA and Western blot analyses revealed identity with RANTES. No other heparin-binding Eo chemotaxin could be identified. HPLC analysis of pooled lesional scale extracts of patients with atopic dermatitis showed fractions containing only weak heparin-binding Eo-chemotactic activity, which, however, showed RANTES immunoreactivity. In experiments to elucidate the putative cellular origin of Eo-attracting chemokines in human skin we investigated supernatants of atopic skin we investigated supernatants of atopic skin-derived T lymphocytes as well as supernatants of stimulated dermal fibroblasts for Eo-chemotactic factors. Unexpectedly, we did not find any heparin-bound Eo attractants in supernatants of stimulated cultured atopic skin-derived T lymphocyte clones, whereas fibroblasts produced RANTES as well as granulocyte-macrophage colony-stimulating factor. Therefore, fibroblasts are likely source of eosinophil attractant cells, which could contribute to the Eo infiltrate. Selectivity of the infiltrate might come from selective induction of RANTES and/or induction of other as yet unidentified Eo-specific chemokines.
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PMID:Role of eosinophil-chemotactic C-C chemokines in cutaneous inflammation. 855 57

Despite normal concentrations of serum eosinophilopoietic cytokines, blood eosinophilia was noted in patients with atopic dermatitis (AD) (n = 32). Significant increase of EG2+ "activated" eosinophil numbers that are mirrored in serum eosinophil cationic protein (ECP) levels in vitro, though not always in synchrony with total eosinophil counts, was also demonstrated. Functionally, AD-source eosinophils showed an enhanced MCLA-dependent chemiluminescence (MDCL) responsiveness to the eosinophilopoietic cytokines, with the characteristics that interleukin-5 (IL-5)-induced MDCL responses strongly correlated with EG2+ eosinophil proportions, whereas both IL-3- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced MDCL responses rather significantly correlated with the degree of blood eosinophilia. Like other eosinophil-associated parameters (total eosinophil counts, EG2+ eosinophil counts and serum ECP levels), those cytokine-induced eosinophil MDCL responses significantly increased in correlation to the AD severity. These results suggest that i) eosinophilopoiesis accompanying development of both IL-3- and GM-CSF-sensitive eosinophils within the bone marrow, and induction of IL-5-sensitive/EG2-reactive eosinophils in the periphery may be regulated through inflammatory events in AD lesional skin; ii) it is unlikely that these eosinophil in vivo differentiation may be due to direct effect of locally synthesized three eosinophilopoietic cytokines; and iii) enhanced sensitivity of EG2+ eosinophils for IL-5 may be responsible for elevated levels of serum ECP in vitro.
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PMID:Increased sensitivity of eosinophils for eosinophilopoietic cytokines in atopic dermatitis. 866 90

Atopic dermatitis (AD), a chronic inflammatory skin disease, is frequently seen in patients with a personal or family history of asthma and allergic rhinitis. Population studies suggest an increasing prevalence of AD in children since World War II, with 10-15% of the population being affected by AD at some time during childhood. In patients with moderate to severe AD, involvement can be life-long, causing significant interference with school, work and social interactions. The term atopic dermatitis was introduced to reflect the close association between AD and respiratory allergy. During the past decade, extraordinary progress has been made in our understanding of the immunopathogenesis of allergic diseases. In particular, this constellation of inherited illnesses has now been demonstrated to be associated with activation of a specific group of cytokine genes encompassing IL-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The molecular basis for selective activation of this cytokine gene cluster and the immunological consequences are now being pursued actively by many laboratories. However, it is clear that allergic diseases result from a polygenic inheritance pattern which involves not only cytokine gene activation but also activation of other less well defined gene products. Furthermore, the clinical expression of allergic diseases is highly dependent on a complex interaction between the host and its environment, e.g. allergen exposure. The genetic predisposition to develop allergic responses may be similar in patients with AD and other allergic diseases, such as asthma. However, targeting of the allergic immune response may relate to the organ in which allergen sensitization first occurs; the capacity of immune effector cells, e.g. T lymphocytes, to home preferentially to the skin versus the respiratory mucosa; and the programmed response of resident cells, e.g. epithelial cells, to injury and inflammation. This review examines the cellular and immunological mechanisms that are thought to play an important role in the pathogenesis of chronic AD. An understanding of the immunological basis of AD is likely to have important clinical implications in our approach to the management of this common illness, and the development of immunomodulators for its treatment.
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PMID:Atopic dermatitis: immunobiology and treatment with immune modulators. 902 Sep 32

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine, is up-regulated in a number of chronic skin inflammatory diseases, particularly atopic dermatitis. However, its role in these conditions remains largely unclear. To explore its function, we have established a rat intradermal transgene model by using a replication-deficient adenoviral vector expressing GM-CSF. Intradermal GM-CSF gene transfer led to a prolonged compartmentalized expression of transgene protein in the dermis. This expression induced an unexpectedly wide spectrum of pathologies in both epidermis and dermis, including neutrophilia, epidermal hyperplasia (acanthosis), an increased number of epidermal Langerhans' cells, accumulation of MHC II-positive macrophages, as well as mild eosinophilia in the dermis at earlier stages and upper dermal fibrosis at later stages. These findings thus identify GM-CSF as a potent multifunctional cytokine at skin site that is capable of evolving numerous inflammatory processes ranging from the early acute neutrophilia to later chronic fibrotic responses, and also suggest the important role of this cytokine in the development and perpetuation of pathologic changes in chronic skin inflammatory conditions including chronic atopic dermatitis. In addition, our study presents a novel model of adult normal animals that is useful for identifying and studying key cytokines involved in inflammatory skin diseases.
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PMID:Intradermal transgenic expression of granulocyte-macrophage colony-stimulating factor induces neutrophilia, epidermal hyperplasia, Langerhans' cell/macrophage accumulation, and dermal fibrosis. 942 99

Topical administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) into the subcutaneous tissue or in the pulmonary alveoli of the rat induces a fibrotic reaction characterized by the presence of alpha-smooth muscle actin-rich myofibroblasts, suggesting that GM-CSF plays a role in the development of fibrotic changes. A high level of expression of GM-CSF also has been demonstrated in epidermal cells during human atopic dermatitis. It is accepted that transforming growth factor beta1 (TGF-beta1) plays a key role in the modulation from fibroblast into myofibroblast, although it is not known how TGF-beta1 activity is stimulated. Up until now, no evidence of early GM-CSF expression during development of fibrosis has been reported. Herein we have studied, using RT-competitive PCR, the expression of GM-CSF mRNA during the early steps of pulmonary fibrosis development after intra-alveolar instillation of bleomycin, a well-established experimental model of this lesion. GM-CSF mRNA was already increased in the total lung at 6 hours and maximal at 12 hours after bleomycin instillation and returned to basal levels at 24 hours. This was followed by an increase of TGF-beta1 and TGF-beta receptor type II (but not of types I and III) mRNAs. Analyses of macrophages and polymorphonuclear neutrophils isolated by bronchoalveolar lavage 12 hours after bleomycin instillation indicated that they were responsible, at least in part, for the accumulation of GM-CSF mRNA. Our results show for the first time that GM-CSF is expressed, very early and temporarily, by inflammatory cells accumulating in the alveolus after bleomycin administration and before the appearance of TGF-beta1. Moreover, we have shown that GM-CSF induces the expression of TGF-beta1 mRNA by alveolar macrophages. Our data support the possibility that GM-CSF participates in the initial steps of the chain of events leading to fibrosis, perhaps through a stimulation of TGF-beta1 production.
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PMID:Early granulocyte-macrophage colony-stimulating factor expression by alveolar inflammatory cells during bleomycin-induced rat lung fibrosis. 988 49

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is released by keratinocytes in sizeable amounts only under pathological conditions, e.g., after topical application of a tumor promoter, in atopic dermatitis (AD), and after wounding. To study the biological function of this cytokine release, we generated transgenic mice that constitutively overexpress GM-CSF in the epidermis. An increase in the numbers of mast cells and Langerhans cells (LCs) in transgenics versus nontransgenic controls was observed but no severe inflammation. This is consistent with a central role of this cytokine in the development and maturation of LCs. Mitotic activity in the epidemnis of transgenic mice was elevated, but epidermal thickness and differentiation were normal. Homeostasis is maintained by an increase of apoptosis in the epidermis. We describe the differential expression of regulators of apoptosis and discuss a potential mechanism for this novel proapoptotic activity of GM-CSF on keratinocytes. Both stimulation of proliferation and promotion of apoptosis are of great relevance to tumorigenesis. The latter may be a means of removing damaged cells after genotoxic stress or injury.
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PMID:Epidermal overexpression of granulocyte-macrophage colony-stimulating factor induces both keratinocyte proliferation and apoptosis. 1071 67

Inflammatory dendritic epidermal cells present in skin lesions of the atopic eczema/dermatitis syndrome display the highest expression of the high-affinity receptor for IgE (FcepsilonRI), ever detected on human antigen-presenting cells. Owing to the instability of the FcepsilonRI (alphagammagamma) complex and fast cleavage from the cell surface during the interleukin-4/granulocyte-macrophage colony-stimulating factor driven in vitro differentiation of monocytes, a method to generate inflammatory dendritic epidermal cells was not at our disposal in the past and the amount of ex vivo isolated inflammatory dendritic epidermal cells available for functional assays was limited. Therefore, information about the role of inflammatory dendritic epidermal cells and FcepsilonRI on this dendritic cell subtype in atopic and inflammatory skin diseases is completely missing. In this study, we were able to: (i) increase the expression of a functional FcepsilonRI complex on the cell surface of immature monocyte-derived dendritic cells from atopic donors by creating a reducing microenvironment; (ii) enhance significantly the intracellular pool of the FcepsilonRIgamma chains, which is the limiting parameter for the FcepsilonRI surface expression; and (iii) generate monocyte-derived dendritic cells displaying the phenotypical characteristics of inflammatory dendritic epidermal cells, producing high amounts of proinflammatory cytokines and chemokines similar to the cytokines found in lesional skin of the atopic eczema/dermatitis syndrome. Altogether the high expression of functional FcepsilonRI on these cells enables us for the first time to study inflammatory dendritic epidermal cells and FcepsilonRI-mediated mechanisms of inflammatory dendritic epidermal cells in vitro, in order to shed light on the putative role of this important cell type in the atopic eczema/dermatitis syndrome.
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PMID:A reducing microenvironment leads to the generation of FcepsilonRIhigh inflammatory dendritic epidermal cells (IDEC). 1240 29

Antigen challenge by patch ovalbumin emulsion induced an eczema-like skin lesion in epicutaneously sensitized guinea pigs. Diseased skin sites were macroscopically characterized by manifestations of dermatitis, such as erythema, edema, and papules, and microscopically characterized by acanthosis, spongiosis, and dermal infiltration by eosinophils. Using such lesions as a model of eczema, we evaluated the potential value of TAK-427 [2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino] imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate] as a therapeutic agent for atopic dermatitis by comparing it with dexamethasone and antihistamines. TAK-427 (0.3-30 mg/kg, p.o.) and dexamethasone (3 and 10 mg/kg, p.o.) inhibited eosinophil infiltration into the skin and ameliorated the dermatitis manifestations and epidermal damage. By contrast, none of the antihistamines tested (azelastine, ketotifen, terfenadine, and cetirizine) suppressed the eosinophil infiltration or dermatitis manifestations. To elucidate the mechanism by which TAK-427 inhibited the development of eczema, we investigated cytokine expression in the affected skin. Both TAK-427 and dexamethasone suppressed the increased mRNA expression of interleukin (IL)-13, granulocyte-macrophage colony-stimulating factor, IL-1alpha, tumor necrosis factor-alpha, interferon-gamma, and IL-8, but not IL-10, suggesting that TAK-427 inhibits allergic inflammation of the skin leading to the development of eczema by inhibiting the expression of proinflammatory cytokines after antigen challenge.
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PMID:Inhibition of allergic dermal inflammation by the novel imidazopyridazine derivative TAK-427 in a guinea pig experimental model of eczema. 1243 53

Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in allergic inflammation including asthma and atopic dermatitis. A newly synthesized compound, YM-90709, 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino [2,3-b]quinoxaline, is reported here to inhibit the binding of IL-5 to its receptor on peripheral human eosinophils and butyric acid-treated eosinophilic HL-60 clone 15 cells, with IC50 values of 1.0 and 0.57 microM, respectively. In contrast, YM-90709 did not affect the binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on eosinophils and eosinophilic HL-60 clone 15 cells. In functional assays, YM-90709 inhibited IL-5-prolonged eosinophil survival with an IC50 value of 0.45 microM and did not affect the GM-CSF-prolonged eosinophil survival. Furthermore, YM-90709 inhibited the IL-5-induced but not GM-CSF-induced tyrosine phosphorylation of Janus kinase 2 (JAK2) in eosinophilic HL-60 clone 15 cells. These results indicate that YM-90709 is a novel IL-5 inhibitor which selectively blocks the binding of IL-5 to the IL-5 receptor (IL-5R).
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PMID:Characterization of YM-90709 as a novel antagonist which inhibits the binding of interleukin-5 to interleukin-5 receptor. 1246 43


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