Effects of leukotriene receptor antagonists on monocyte chemotaxis, p38 and cytoplasmic calcium.
Montelukast and zafirlukast, two cysteinyl leukotriene receptor antagonists (LTRAs), have been shown to have a beneficial effect on the clinical symptoms of asthma. LTRAs can inhibit eosinophil recruitment; however, little is known about their role in monocyte migration. We investigated whether montelukast and zafirlukast could suppress chemokine-induced chemotaxis of monocytes and signaling. Chemotaxis of monocytes from peripheral blood mononuclear cells (PBMCs), cord blood mononuclear cells (CBMCs), and THP-1 cells was evaluated using a 24-well transwell microchamber. [Ca2+]i was measured with the fluorescence calcium indicator fura-2/AM photometry system. p38 MAPK expression was measured by Western blotting. Results showed that montelukast (1-100 microm) and zafirlukast (100 microm) significantly down-regulated monocyte chemoattractant protein-1(MCP-1)-induced chemotaxis of THP-1 cells and human primary monocytes from PBMCs and CBMCs (p<0.05, each comparison). Montelukast also abolished MCP-1-induced [Ca2+]i and pp38 MAPK expression in THP-1 cells in a dose-dependent manner. These data demonstrate that montelukast is effective in down-regulating human monocyte chemotaxis induced by MCP-1. This effect may involve the down-regulation of MCP-1-induced [Ca2+]i and p38 MAPK expression.
Hung
Chih-Hsing
CH
Department of Pediatrics, Tri-service General Hospital, National Defense Medical Center, Taipei, and Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Taiwan, Republic of China. pedhung@kmu.edu.fw
Li
Chi-Yuan
CY
Hua
Yi-Ming
YM
Chen
Chun-Jung
CJ
Yang
Kuender D
KD
Jong
Yuh-Jyh
YJ
D000085:Acetates / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002469:Cell Separation; D002633:Chemotaxis / Q000187:drug effects*; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005312:Fetal Blood; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D048448:Phenylcarbamates; D010783:Photometry; D011247:Pregnancy; D011804:Quinolines / Q000494:pharmacology; D012016:Reference Values; D013440:Sulfides; D013449:Sulfonamides; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D011804:Quinolines; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds; D048051:p38 Mitogen-Activated Protein Kinases; C093875:montelukast; D002118:Calcium; C062735:zafirlukast