title: Autocrine abscisic acid plays a key role in quartz-induced macrophage activation.
abstract: Inhalation of quartz induces silicosis, a lung disease where alveolar macrophages release inflammatory mediators, including prostaglandin-E(2) (PGE(2)) and tumor necrosis factor α (TNF-α). Here we report the pivotal role of abscisic acid (ABA), a recently discovered human inflammatory hormone, in silica-induced activation of murine RAW264.7 macrophages and of rat alveolar macrophages (AMs). Stimulation of both RAW264.7 cells and AMs with quartz induced a significant increase of ABA release (5- and 10-fold, respectively), compared to untreated cells. In RAW264.7 cells, autocrine ABA released after quartz stimulation sequentially activates the plasma membrane receptor LANCL2 and NADPH oxidase, generating a Ca(2+) influx resulting in NFκ B nuclear translocation and PGE(2) and TNF-α release (3-, 2-, and 3.5-fold increase, respectively, compared to control, unstimulated cells). Quartz-stimulated RAW264.7 cells silenced for LANCL2 or preincubated with a monoclonal antibody against ABA show an almost complete inhibition of NFκ B nuclear translocation and PGE(2) and TNF-α release compared to controls electroporated with a scramble oligonucleotide or preincubated with an unrelated antibody. AMs showed similar early and late ABA-induced responses as RAW264.7 cells. These findings identify ABA and LANCL2 as key mediators in quartz-induced inflammation, providing possible new targets for antisilicotic therapy.
authors: DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1 16132 Genova, Italy. mirko.magnone@unige.it
authors: Mirko
authors: M
authors: Magnone
authors: Laura
authors: L
authors: Sturla
authors: Emanuela
authors: E
authors: Jacchetti
authors: Sonia
authors: S
authors: Scarfì
authors: Santina
authors: S
authors: Bruzzone
authors: Cesare
authors: C
authors: Usai
authors: Lucrezia
authors: L
authors: Guida
authors: Annalisa
authors: A
authors: Salis
authors: Gianluca
authors: G
authors: Damonte
authors: Antonio
authors: A
authors: De Flora
authors: Elena
authors: E
authors: Zocchi
mesh_terms: D000040:Abscisic Acid / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D011791:Quartz / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: C572254:LANCL2 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D028044:Phosphate-Binding Proteins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D011791:Quartz; D000040:Abscisic Acid; D020122:tert-Butylhydroperoxide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D015232:Dinoprostone; D002118:Calcium