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1.
Clin Exp Dermatol ; 39(1): 54-7, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23782102

ABSTRACT

Vitiligo is a disorder of depigmentation, for which the pathogenesis is as yet unclear. Interleukin (IL)-8 (CXCL8) is a key inflammatory chemokine. We investigated the regulation of IL-8 production in human melanocytes, and the IL-8 serum levels and skin gene expression in patients with vitiligo and in controls. Cultured melanocytes were stimulated for 24 h with tumour necrosis factor (TNF) 100 ng/mL and IL-1ß 10 ng/mL, with or without pretreatment with luteolin 50 µmol/L for 30 min, and IL-8 release was measured by ELISA. Serum cytokines were measured by a microbead array. Skin biopsies were taken from healthy subjects (n = 14) as well as from marginal lesional and nonlesional skin from patients with vitiligo (n = 15). IL-8 gene expression was evaluated by quantitative real time PCR. Both TNF and IL-1ß stimulated significant IL-8 release (P < 0.01) from melanocytes, whereas pretreatment with luteolin significantly inhibited this effect (P < 0.01). IL-8 gene expression was significantly increased in vitiligo compared with control skin (P < 0.05). IL-8 may be involved in vitiligo inflammation. Inhibition by luteolin of IL-8 release could be useful for vitiligo therapy.


Subject(s)
Interleukin-8/metabolism , Luteolin/pharmacology , Melanocytes/drug effects , Vitiligo/metabolism , Adult , Case-Control Studies , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Profiling , Humans , Interleukin-1beta/pharmacology , Interleukin-6/metabolism , Male , Melanocytes/metabolism , Middle Aged , Skin/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Vitiligo/drug therapy
2.
Br J Dermatol ; 169(3): 695-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24033157

ABSTRACT

BACKGROUND: Neurotensin (NT) participates in immune responses, but the mechanisms are not known. We have previously shown that NT augments the ability of corticotropin-releasing hormone (CRH) to increase mast-cell-dependent vascular permeability in rodents. We also showed that NT stimulates human mastcell release of vascular endothelial growth factor, and that CRH is increased in the serum of patients with atopic dermatitis (AD), an inflammatory skin condition involving mast cells. OBJECTIVES: To measure serum levels of NT, and lesional skin expression of NT and the main NT receptor (NTR-1) in AD, and to compare it with skin expression in chronic urticaria (CU) and urticaria pigmentosa (UP). METHODS: Serum NT was measured with a Milliplex microbead array. Skin NT and NTR-1 gene expression was determined with quantitative polymerase chain reaction. Immunohistochemistry was performed using a mouse monoclonal antibody for NT, and a rabbit polyclonal antibody for NTR-1. Mast cells were counterstained with Leder dye. RESULTS: Neurotensin is significantly elevated in the serum of patients with AD compared with healthy controls (P = 0.0001). NT gene expression is also significantly increased in lesional skin of patients with AD compared with controls (P = 0.0194). Moreover, immunohistochemistry of AD lesions shows NT > NTR-1 staining of perivascular cells, many of which are identified as mast cells after staining with Leder dye. There was no statistically significant difference in NT and NTR-1 lesional skin gene expression in patients with either CU or UP. CONCLUSIONS: These results suggest that interactions between NT and mast cells may occur and contribute to AD pathogenesis.


Subject(s)
Dermatitis, Atopic/metabolism , Neurotensin/metabolism , Adult , Dermatitis, Atopic/genetics , Female , Gene Expression , Humans , Immunohistochemistry , Male , Mast Cells/metabolism , Neurotensin/genetics , Real-Time Polymerase Chain Reaction , Receptors, Neurotensin/genetics , Receptors, Neurotensin/metabolism , Skin/metabolism , Urticaria/metabolism , Urticaria Pigmentosa/metabolism
3.
Br J Dermatol ; 166(6): 1349-52, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22283733

ABSTRACT

BACKGROUND: Psoriasis involves skin inflammation that often worsens with stress, but the mechanism of this effect remains obscure. We have shown that corticotropin-releasing hormone (CRH) is increased in the serum of patients with psoriasis. A peptide, neurotensin (NT), can trigger skin histamine release and augment the ability of CRH to increase skin vascular permeability. OBJECTIVES: To investigate the serum level of NT, and the expression of genes for NT and NT receptor-1 (NTR-1) in lesional and nonlesional skin of patients with psoriasis, compared with normal controls. Also, to study the effect of NT on human mast cell release of vascular endothelial growth factor (VEGF), which is increased in psoriatic skin. METHODS: Serum was obtained from patients with psoriasis (n = 56) and controls (n = 33); NT levels were measured with the Milliplex microbead assay. Biopsies were obtained from the lesional and nonlesional skin of patients with chronic plaque psoriasis (n = 40), who had not received any treatment for at least 15 days and were free of any systemic inflammatory diseases. Control skin samples were obtained from healthy subjects (n = 30). Expression of genes for NT and NTR-1 in the skin was evaluated by quantitative reverse transcriptase-polymerase chain reaction. LAD2 human mast cells were stimulated by NT (1 µmol L(-1)) for 24 h and VEGF was measured by enzyme-linked immunosorbent assay. RESULTS: Serum NT was increased in patients with psoriasis, while expression of genes for NT and NTR-1 in lesional skin was decreased compared with controls. NT induced VEGF release from mast cells and was augmented by interleukin-33. CONCLUSION: NT may play a role in psoriasis pathogenesis and its worsening by stress, at least in part through activation of skin mast cells.


Subject(s)
Neurotensin/metabolism , Psoriasis/blood , Adult , Cells, Cultured , Female , Humans , Male , Mast Cells , Middle Aged , Neurotensin/genetics , Psoriasis/genetics , Receptors, Neurotensin/genetics , Receptors, Neurotensin/metabolism , Skin/metabolism , Stress, Psychological/blood , Stress, Psychological/complications , Vascular Endothelial Growth Factor A/metabolism
4.
Clin Exp Dermatol ; 34(5): e163-6, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19094125

ABSTRACT

A 38-year-old woman presented with a pronounced increase in symptoms and proliferation of urticaria pigmentosa (UP) after acute psychological stress, which was quantified using the Spielberger's State-Trait Anxiety Inventory. Immunohistochemical examination of a skin biopsy from a new UP lesion showed a large number of activated mast cells expressing corticotrophin-releasing factor receptor-1 (CRF-R1) and there was high serum CRF. This is the first documented report to our knowledge of UP worsening associated with acute stress, possibly through activation of skin mast-cell CRF-R1.


Subject(s)
Mast Cells/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Skin/metabolism , Stress, Psychological/complications , Urticaria Pigmentosa/etiology , Acute Disease , Adult , Female , Humans , Urticaria Pigmentosa/metabolism , Urticaria Pigmentosa/pathology
5.
Br J Pharmacol ; 155(7): 1076-84, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18806808

ABSTRACT

BACKGROUND AND PURPOSE: Allergic inflammation and autoimmune diseases, such as atopic dermatitis, psoriasis and multiple sclerosis (MS), involve both mast cell and T-cell activation. However, possible interactions between the two and the mechanism of such activations are largely unknown. EXPERIMENTAL APPROACH: Human umbilical cord blood-derived cultured mast cells (hCBMCs) and Jurkat T cells were incubated separately or together, following activation with myelin basic protein (MBP), as well as with or without pretreatment with the flavonoid luteolin for 15 min. The supernatant fluid was assayed for inflammatory mediators released from mast cells and interleukin (IL)-2 release from Jurkat cells. KEY RESULTS: MBP (10 microM) stimulates hCBMCs to release IL-6, IL-8, transforming growth factor (TGF)-beta1, tumour necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), histamine and tryptase (n=6, P<0.05). Addition of mast cells to Jurkat cells activated by anti-CD3/anti-CD28 increases IL-2 release by 30-fold (n=3, P<0.05). MBP-stimulated mast cells and their supernatant fluid further increase Jurkat cell IL-2 release (n=3, P<0.05). Separation of mast cells and activated Jurkat cells by a Transwell permeable membrane inhibits Jurkat cell stimulation by 60%. Pretreatment of Jurkat cells with a TNF-neutralizing antibody reduces IL-2 release by another 40%. Luteolin pretreatment inhibits mast cell activation (n=3-6, P<0.05), Jurkat cell activation and mast cell-dependent Jurkat cell stimulation (n=3, P<0.05). CONCLUSIONS AND IMPLICATIONS: Mast cells can stimulate activated Jurkat cells. This interaction is inhibited by luteolin, suggesting that this flavonoid may be useful in the treatment of autoimmune diseases.


Subject(s)
Jurkat Cells/drug effects , Luteolin/pharmacology , Mast Cells/drug effects , Myelin Basic Protein/antagonists & inhibitors , Cells, Cultured , Humans , Inflammation Mediators/metabolism , Interleukin-2/metabolism , Jurkat Cells/metabolism , Mast Cells/immunology , Myelin Basic Protein/metabolism , Tryptases/drug effects , Tryptases/metabolism
6.
Int J Immunopathol Pharmacol ; 20(1): 69-74, 2007.
Article in English | MEDLINE | ID: mdl-17346429

ABSTRACT

Myocardial ischemia-reperfusion (IR) injury complicates all forms of coronary artery revascularization. Circulating interleukin-6 (IL-6) has been implicated in cell death following a variety of stimuli. Macrophages, platelets, neutrophils and the endothelium have been shown to release IL-6 after IR injury. Cardiac mast cells have been implicated in IR; however, their involvement has never been quantified. In this randomized, prospective study, we compared cardiac tissue susceptibility and serum IL-6 changes between mast cell deficient (W/Wv) mice and their normal littermates (+/+). Twenty-eight male W/Wv mice (n=14) and their +/+ littermates (n=14) were anaesthetized with 2.5% isoflurane. The left coronary artery (LCA) was ligated for 30 minutes or a sham procedure was performed. After 6 hours of reperfusion, the animals were sacrificed. The muscle viability was assessed on fresh whole-mount slices by nitroblue tetrazolium (NBT) histochemical assay and serum IL-6 concentrations measured by ELISA. Cardiac muscle viability was significantly higher in W/Wv mice than the +/+ mice. Serum IL-6 levels were higher in the +/+ sham mice (465 +/- 32 pg/ml, n=6) than the W/Wv mice (185 +/- 31 pg/ml, n=6), p < 0.001. The IL-6 levels increased significantly after reperfusion only in the +/+ mice (698 +/- 41 pg/ml, n=8, p = 0.001), while it remained similar in the W/Wv mice (202 +/- 48 pg/ml, n=8, p = 0.783). These results show that the absence of mast cells reduces the myocardial damage associated with IR injury. Furthermore, there is an attenuation in the inflammatory response, as measured by serum IL-6 levels, following this local insult. This finding entertains the prospect of developing prophylactic therapy--targeting selective inhibition of cardiac mast cell activation, in clinical situations involving medical or surgical myocardial revascularization.


Subject(s)
Interleukin-6/blood , Mast Cells/physiology , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Animals , Enzyme-Linked Immunosorbent Assay , Male , Mice , Necrosis , Nitroblue Tetrazolium
7.
Int J Immunopathol Pharmacol ; 19(4): 787-94, 2006.
Article in English | MEDLINE | ID: mdl-17166400

ABSTRACT

Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.


Subject(s)
Mast Cells/drug effects , Progesterone/pharmacology , Animals , Male , Mast Cells/metabolism , Rats , Rats, Sprague-Dawley
8.
Stem Cell Rev ; 2(2): 143-54, 2006.
Article in English | MEDLINE | ID: mdl-17237553

ABSTRACT

Findings obtained using animal models have often failed to reflect the processes involved in human disease. Moreover, human cultured cells do not necessarily function as their actual tissue counterparts. Therefore, there is great demand for sources of human progenitor cells that may be directed to acquire specific tissue characteristics and be available in sufficient quantities to carry out functional and pharmacological studies. Acase in point is the mast cell, well known for its involvement in allergic reactions, but also implicated in inflammatory diseases. Mast cells can be activated by allergens, anaphylatoxins, immunoglobulin-free light chains, superantigens, neuropeptides, and cytokines, leading to selective release of mediators. These could be involved in many inflammatory diseases, such as asthma and atopic dermatitis, which worsen by stress, through activation by local release of corticotropin-releasing hormone or related peptides. Umbilical cord blood and cord matrix-derived mast cell progenitors can be separated magnetically and grown in the presence of stem cell factor, interleukin-6, interleukin-4, and other cytokines to yield distinct mast cell populations. The recent use of live cell array, with its ability to study such interactions rapidly at the single-cell level, provides unique new opportunities for fast output screening of mast cell triggers and inhibitors.


Subject(s)
Fetal Blood/cytology , Mast Cells/cytology , Models, Biological , Neurosecretory Systems/immunology , Humans , Inflammation/diagnosis , Neurosecretory Systems/cytology , Tissue Array Analysis
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