title: Lipopolysaccharide enhances FcεRI-mediated mast cell degranulation by increasing Ca2+ entry through store-operated Ca2+ channels: implications for lipopolysaccharide exacerbating allergic asthma.
abstract: Lipopolysaccharide (LPS) can exacerbate asthma; however, the mechanisms are not fully understood. This study investigated the effect of LPS on antigen-stimulated mast cell degranulation and the underlying mechanisms. We found that LPS enhanced degranulation in RBL-2H3 cells and mouse peritoneal mast cells upon FcεRI activation, in a dose- and time-dependent manner. Parallel to the alteration of degranulation, LPS increased FcεRI-activated Ca(2+) mobilization, as well as Ca(2+) entry through store-operated calcium channels (SOCs) evoked by thapsigargin. Blocking Ca(2+) entry through SOCs completely abolished LPS enhancement of mast cell degranulation. Consistent with functional alteration of SOCs, LPS increased mRNA and protein levels of Orai1 and STIM1, two major subunits of SOCs, in a time-dependent manner. In addition, LPS increased the mRNA level of Toll-like receptor 4 (TLR4) in a time-dependent manner. Blocking TLR4 with Cli-095 inhibited LPS, increasing transcription and expression of SOC subunits. Concomitantly, the effect of LPS enhancement of Ca(2+) mobilization and mast cell degranulation was largely reduced by Cli-095. Administration of LPS (1 μg) in vivo aggravated airway hyperreactivity and inflammatory reactions in allergic asthmatic mice. Histamine levels in serum and bronchoalveolar lavage fluid were increased by LPS treatment. In addition, Ca(2+) mobilization was enhanced in peritoneal mast cells isolated from LPS-treated asthmatic mice. Taken together, these results imply that LPS enhances mast cell degranulation, which potentially contributes to LPS exacerbating allergic asthma. Lipopolysaccharide increases Ca(2+) entry through SOCs by upregulating transcription and expression of SOC subunits, mainly through interacting with TLR4 in mast cells, resulting in enhancement of mast cell degranulation upon antigen stimulation.
authors.affiliation: State Key Laboratory of Respiratory Disease for Allergy, Shengzhen University, China.
authors.forename: Chengbin
authors.initials: C
authors.lastname: Yang
authors.forename: Xucheng
authors.initials: X
authors.lastname: Mo
authors.forename: Jingzhang
authors.initials: J
authors.lastname: Lv
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.forename: Meichun
authors.initials: M
authors.lastname: Yuan
authors.forename: Ming
authors.initials: M
authors.lastname: Dong
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xinping
authors.initials: X
authors.lastname: Luo
authors.forename: Xinmin
authors.initials: X
authors.lastname: Fan
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000071740:ORAI1 Protein; D010047:Ovalbumin; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; D012333:RNA, Messenger; D017455:Receptors, IgE; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D006632:Histamine; D010047:Ovalbumin; D000252:Calcium-Transporting ATPases