Aspirin and salicylates modulate IgE-mediated leukotriene secretion in mast cells through a dihydropyridine receptor-mediated Ca(2+) influx.
Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that may potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance. Aspirin intolerance is accompanied by increased leukotriene (LT) synthesis, and high levels of serum IgE are a risk factor for NSAID sensitivity. Here we demonstrate that aspirin modulates LTC(4) secretion in mast cells. Therapeutic levels of aspirin and salicylates (<or=0.3 mM, i.e., the concentrations observed in vivo in the use of antipyretic analgesic) increased IgE-mediated LTC(4) secretion. Aspirin-induced stimulation was accompanied by increased Ser-505 phosphorylation of cytosolic phospholipase A(2), which occurred independently of extracellular signal-regulated protein kinase-1/2 and p38 mitogen-activated protein kinase pathways. Aspirin also increased IgE-mediated Ca(2+) influx, whereas aspirin at concentrations of >or=0.3 mM dose-dependently reduced Ca(2+) store emptying and Ca(2+) release-activated Ca(2+) channel activation. Instead, aspirin facilitated a dihydropyridine receptor-mediated Ca(2+) influx, resulting in increased LTC(4) secretion. This novel action of aspirin may play roles in exacerbation of immediate allergy and aspirin intolerance.
Togo
Kana
K
Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, Itabashi-Ku, Tokyo, Japan.
Suzuki
Yoshihiro
Y
Yoshimaru
Tetsuro
T
Inoue
Toshio
T
Terui
Tadashi
T
Ochiai
Toyoko
T
Ra
Chisei
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005470:Fluorometry; D007073:Immunoglobulin E / Q000276:immunology*; D017997:Leukotriene C4 / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008809:Mice, Inbred C3H; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020746:Calcium Channels, L-Type; D012459:Salicylates; D017997:Leukotriene C4; D007073:Immunoglobulin E; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; D001241:Aspirin; D002118:Calcium