title: Molecular regulation of interleukin-13 and monocyte chemoattractant protein-1 expression in human mast cells by interleukin-1beta.
abstract: Mast cells play pivotal roles in immunoglobulin (Ig) E-mediated airway inflammation, expressing interleukin (IL)-13 and monocyte chemoattractant protein-1 (MCP-1), which in turn regulate IgE synthesis and/or inflammatory cell recruitment. The molecular effects of IL-1beta on cytokine expression by human mast cells (HMC) have not been studied well. In this report, we provide evidence that human umbilical cord blood-derived mast cells (CBDMC) and HMC-1 cells express the type 1 receptor for IL-1. We also demonstrate that IL-1beta and tumor necrosis factor-alpha are able to induce, individually or additively, dose-dependent expression of IL-13 and MCP-1 in these cells. The induction of IL-13 and MCP-1 gene expression by IL-1beta was accompanied by the activation of IL-1 receptor-associated kinase and translocation of the transcription factor, nuclear factor (NF) kappaB into the nucleus. Accordingly, Bay-11 7082, an inhibitor of NF-kappaB activation, inhibited IL-1beta-induced IL-13 and MCP-1 expression. IL-1beta also induced IL-13 promoter activity while enhancing the stability of IL-13 messenger RNA transcripts. Dexamethasone, a glucocorticoid, inhibited IL-1beta-induced nuclear translocation of NF-kappaB and also the secretion of IL-13 from mast cells. Our data suggest that IL-1beta can serve as a pivotal costimulus of inflammatory cytokine synthesis in human mast cells, and this may be partly mediated by IL-1 receptor-binding and subsequent signaling via nuclear translocation of NF-kappaB. Because IL-1beta is a ubiquitously expressed cytokine, these findings have important implications for non-IgE-mediated signaling in airway mast cells as well as for innate immunity and airway inflammatory responses, such as observed in extrinsic and intrinsic asthma.
authors.affiliation: Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee 37614-1709, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lee
authors.forename: S Matthew
authors.initials: SM
authors.lastname: Fitzgerald
authors.forename: Shau K
authors.initials: SK
authors.lastname: Huang
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
authors.forename: David S
authors.initials: DS
authors.lastname: Chi
authors.forename: Denise M
authors.initials: DM
authors.lastname: Milhorn
authors.forename: Guha
authors.initials: G
authors.lastname: Krishnaswamy
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D018793:Interleukin-13; D016328:NF-kappa B; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases