Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells.
We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is comitogenic with insulin-like growth factors (IGF) in airway smooth muscle (ASM) cells. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced inhibitory IGF-binding proteins (IGFBP). In this report, we analyzed the conditioned media (CM) from LTD4-treated human ASM cells (ASM-LTD4-CM) by Western ligand blotting and demonstrated a marked LTD4-induced reduction in the levels of the intact IGFBP (predominantly IGFBP-2) secreted by these cells. The IGFBP-2 in the ASM-LTD4-CM was identified as lower-molecular-weight fragments by Western immunoblotting. Incubation with 125I-labeled IGFBP demonstrated that an IGFBP protease was induced in the ASM cells in response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti-matrix metalloproteinase (MMP)-1 antibodies demonstrated a dose-dependent reduction of IGFBP proteolysis. Tissue inhibitor of MMP-1 and Batimastat (synthetic) inhibited proteolysis of IGFBP. Immunoblotting the ASM-LTD4-CM with anti-MMP-1 demonstrated a dose-dependent increase in MMP-1 protein. Similar results were also obtained by immunocytochemistry. Collectively, these observations demonstrate that MMP-1 is an IGFBP protease induced by leukotrienes that plays a significant role in modulating IGF action in ASM cells. A similar mechanism may be applicable in vivo in the airways of patients with asthma.
Rajah
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Division of Endocrinology, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
Nunn
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Herrick
D J
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Grunstein
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Cohen
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D001980:Bronchi / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism*; D017077:Culture Media, Conditioned; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*
D017077:Culture Media, Conditioned; D007334:Insulin-Like Growth Factor I; D017998:Leukotriene D4; D010450:Endopeptidases; C095329:IGFBP-2 protease; D017364:Collagenases; D020781:Matrix Metalloproteinase 1