Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts.
BACKGROUND
Cysteinyl leukotrienes (cys-LTs) are potent asthma-related mediators that function through their G protein-coupled receptors, cys-LT receptor type 1 (CysLT1R) and cys-LT receptor type 2 (CysLT2R).


OBJECTIVE
Because many G protein-coupled receptors transactivate the epidermal growth factor receptor (EGFR) through metalloprotease-mediated ligand shedding, we investigated the effects of cys-LTs on signal transduction and proliferation of bronchial fibroblasts.


METHODS
Human bronchial fibroblasts were grown from biopsy specimens of healthy subjects. Mitogenesis was assessed on the basis of tritiated methylthymidine incorporation.


RESULTS
Leukotriene (LT) D(4) alone did not increase mitogenesis but dose-dependently increased thymidine incorporation and cell proliferation in the presence of epidermal growth factor (EGF). The enhancement was not prevented by CysLT1R antagonists (MK-571 and montelukast) or by a dual antagonist (BAY u9773), which is consistent with the lack of detectable mRNA for CysLT1R and CysLT2R in bronchial fibroblasts. LTD(4) did not cause EGFR transphosphorylation nor was the synergism blocked by the metalloprotease inhibitor GM6001. The EGFR-selective kinase inhibitor AG1478 suppressed the synergy between LTD(4) and EGF but had no effect on synergistic interactions of LTD(4) with other receptor tyrosine kinase growth factors. The effect of LTD(4) involved a pertussis toxin-sensitive and protein kinase C-mediated intracellular pathway, leading to sustained growth factor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase B (PKB/Akt).


CONCLUSIONS
Cys-LTs do not transactivate EGFR but have a broader capability to synergize with receptor tyrosine kinase pathways.


CONCLUSIONS
This study implies a critical role of cys-LTs in airway fibrosis in asthma and other chronic airway diseases, which might not be blocked by therapy with current LT receptor antagonists.
Yoshisue
Hajime
H
Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, UK. H.Yoshisue@soton.ac.uk
Kirkham-Brown
Jody
J
Healy
Eugene
E
Holgate
Stephen T
ST
Sampson
Anthony P
AP
Davies
Donna E
DE
D000085:Acetates / Q000494:pharmacology; D001980:Bronchi; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D017997:Leukotriene C4 / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D013440:Sulfides
D000085:Acetates; C071435:BAY u9773; D003521:Cyclopropanes; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D013189:SRS-A; D013440:Sulfides; D017997:Leukotriene C4; C059141:verlukast; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C083169:leukotriene D4 receptor; C093875:montelukast