title: Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells.
abstract: Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5-2 μM) for 6 hours significantly increases corticotropin-releasing hormone receptor-1 (CRHR-1) mRNA and protein expression. Addition of CRH (1 μM) to LAD2 cells, which are "primed" with SP for 48 hours and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) 24 hours later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1 μM) for 6 hours induces gene expression of NK-1 as compared with controls. However, repeated stimulation of mast cells with CRH (1 μM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Asadi
authors.forename: Konstantinos-Dionysios
authors.initials: KD
authors.lastname: Alysandratos
authors.forename: Asimenia
authors.initials: A
authors.lastname: Angelidou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Miniati
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Sismanopoulos
authors.forename: Magdalini
authors.initials: M
authors.lastname: Vasiadi
authors.forename: Bodi
authors.initials: B
authors.lastname: Zhang
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kalogeromitros
authors.forename: Theoharis C
authors.initials: TC
authors.lastname: Theoharides
mesh_terms: D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D013373:Substance P / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D016209:Interleukin-8; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D018040:Receptors, Neurokinin-1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013373:Substance P; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
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