IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin.

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 microM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.

Rupatadine inhibits proinflammatory mediator secretion from human mast cells triggered by different stimuli.

BACKGROUND: Mast cells are involved in allergy and inflammation by secreting multiple mediators including histamine, cytokines and platelet-activating factor. Certain histamine 1 receptor antagonists have been reported to inhibit histamine secretion, but the effect on cytokine release from human mast cells triggered by allergic and other stimuli is not well known. We investigated the ability of rupatadine, a potent histamine 1 receptor antagonist that also blocks platelet-activating factor actions, to also inhibit mast cell mediator release. METHODS: Rupatadine (1-50 microM) was used before stimulation by: (1) interleukin (IL)-1 to induce IL-6 from human leukemic mast cells (HMC-1 cells), (2) substance P for histamine, IL-8 and vascular endothelial growth factor release from LAD2 cells, and (3) IgE/anti-IgE for cytokine release from human cord blood-derived cultured mast cells. Mediators were measured in the supernatant fluid by ELISA or by Milliplex microbead arrays. RESULTS: Rupatadine (10-50 microM) inhibited IL-6 release (80% at 50 microM) from HMC-1 cells, whether added 10 min or 24 h prior to stimulation. Rupatadine (10-50 microM for 10 min) inhibited IL-8 (80%), vascular endothelial growth factor (73%) and histamine (88%) release from LAD2 cells, as well as IL-6, IL-8, IL-10, IL-13 and tumor necrosis factor release from human cord blood-derived cultured mast cells. CONCLUSION: Rupatadine can inhibit histamine and cytokine secretion from human mast cells in response to allergic, immune and neuropeptide triggers. These actions endow rupatadine with unique properties in treating allergic inflammation, especially perennial rhinitis and idiopathic urticaria.

Etiologic aspects and prognostic factors of patients with chronic urticaria: nonrandomized, prospective, descriptive study.

BACKGROUND: Studies investigating etiologic factors in chronic urticaria are based on small populations of a few hundred patients. In addition, data on prognostic factors of the disorder are scarce. OBJECTIVE: To investigate the etiologic and prognostic factors of chronic urticaria on a large population referred to tertiary specialized hospital departments. METHODS: The study investigated 2,523 patients with chronic urticaria and a negative autologous serum skin test using anamnesis, and the literature suggested laboratory tests for etiologic factors of the disorder. The patients were prescribed cetirizine 10 mg daily plus treatment of any underlying disorders illuminated by the laboratory investigation. The rescue medicine was loratadine 10 mg. The patients were evaluated every 3 months. Comparative statistical methods were used to evaluate the prognostic factors having an impact on the duration of the disorder until resolution of symptoms. RESULTS: Etiologic factors of chronic urticaria-angioedema were identified in 38.7% of the patients. Physical urticarias had a prevalence of 17.1% in the population under study. Other common etiologic factors identified included infection (7.7%) and autoimmune thyropathy (7.3%). Multiple regression analysis showed that female gender, long duration of the disorder at the initial examination, the presence of angioedema, and physical urticarias are associated with worse prognosis of the disorder, whereas increased self-reported stress and psychiatric disease had no impact on the course of the disorder. CONCLUSION: A detailed medical history and selective laboratory tests can illuminate etiologic factors in less than 40% of patients with chronic urticaria. Prognostic factors identified to impact the natural history of the disorder could be helpful when designing studies assessing the efficacy of therapeutic agents for chronic urticaria.

Impact of stress and mast cells on brain metastases.

Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.

Cutaneous granulomas with predominantly CD8(+) lymphocytic infiltrate in a child with severe combined immunodeficiency.

BACKGROUND: Combined immunodeficiency disorders comprise a heterogeneous group of diseases characterized by both humoral and cell-mediated immunodeficiency. Cutaneous granulomas manifestations in children with combined immunodeficiency are rare. OBJECTIVE: We report the case of a 6-year-old boy who presented with disseminated cutaneous granulomas and a history of multiple infections. METHODS AND RESULTS: Laboratory evaluation revealed severe combined immunodeficiency, and deoxyribonucleic acid (DNA) analysis confirmed mutations on a gene of chromosome 19 that encodes an enzyme called Janus kinase 3 (Jak-3). Immunohistochemistry revealed expression of CD8(+) in the perivascular lymphocytic infiltrate CONCLUSION: Disseminated granulomatous lesions in children with a history of frequent infections should prompt the clinician to initiate detailed immunocompetence evaluation as they might prove to be the first manifestation of immunologic impairment.

Differential release of mast cell mediators and the pathogenesis of inflammation.

Mast cells are well known for their involvement in allergic and anaphylactic reactions, during which immunoglobulin E (IgE) receptor (Fc epsilon RI) aggregation leads to exocytosis of the content of secretory granules (1000 nm), commonly known as degranulation, and secretion of multiple mediators. Recent findings implicate mast cells also in inflammatory diseases, such as multiple sclerosis, where mast cells appear to be intact by light microscopy. Mast cells can be activated by bacterial or viral antigens, cytokines, growth factors, and hormones, leading to differential release of distinct mediators without degranulation. This process appears to involve de novo synthesis of mediators, such as interleukin-6 and vascular endothelial growth factor, with release through secretory vesicles (50 nm), similar to those in synaptic transmission. Moreover, the signal transduction steps necessary for this process appear to be largely distinct from those known in Fc epsilon RI-dependent degranulation. How these differential mast cell responses are controlled is still unresolved. No clinically available pharmacological agents can inhibit either degranulation or mast cell mediator release. Understanding this process could help develop mast cell inhibitors of selective mediator release with novel therapeutic applications.

Secondary anetoderma associated with mastocytosis.

BACKGROUND: Mastocytosis represents a wide spectrum of proliferative disorders of mast cells in the bone marrow, skin and/or internal organs. The most common manifestation is urticaria pigmentosa (UP), which is characterized by small or large brown-red maculopapules on the skin. Occasionally, elastic and collagen fibers in the lesions degenerate and result in a lax area of skin termed anetoderma. METHODS: We report a 21-year-old male patient with multiple cutaneous anetodermic lesions, present since infancy, at UP sites confirmed with histochemistry. RESULTS: Urinary N-methyl 24-hour histamine levels were elevated, but serum tryptase levels were within normal limits. Radiologic examination of long bones was unremarkable, as well as all other blood results. UP biopsy showed absence of epidermal involvement and increased number of mast cells located perivascularly. There was fragmentation of elastic fibers in the papillary dermis. CONCLUSIONS: A patient with multiple cutaneous anetodermic lesions, presented since infancy, led to the diagnosis of UP. Such an association is rare and raises intriguing questions concerning the pathogenesis of anetoderma.