Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis.
The insulin-like growth factor (IGF) axis is involved in regulating proliferation in a variety of cell types, including airway smooth muscle. Because airway hyperplasia is a characteristic feature of asthma and other lung diseases, we examined the interaction of the potent proinflammatory eicosanoid leukotriene D4 (LTD4) with the IGF axis in regulating airway smooth muscle cell mitogenesis. In cultured rabbit airway smooth muscle cells, IGF-I but not LTD4 was mitogenic at submaximal concentrations. The combination of the two agents exerted a significant synergistic effect on airway smooth muscle cell mitogenesis. Analysis of airway smooth muscle cell conditioned medium by Western ligand blotting demonstrated a marked LTD4-induced reduction in the levels of the predominant IGF binding protein IGFBP-2, which is elaborated into the conditioned medium. The latter effect on IGFBP-2 release was not associated with a reduction in IGFBP-2 mRNA levels; however, LTD4-treated airway smooth muscle conditioned medium demonstrated the presence of a lower molecular weight form of IGFBP-2 by cross-linking to IGFs and specific proteolysis of radiolabeled IGFBP-2. IGFBP-2 was also noted to be associated with airway smooth muscle cell membranes, where it was protected from LTD4-induced proteolysis. Finally, exogenous administration of IGFBP-2 was found to inhibit the promitogenic effect of IGF-I in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Cohen
P
P
Division of Endocrinology, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
Noveral
J P
JP
Bhala
A
A
Nunn
S E
SE
Herrick
D J
DJ
Grunstein
M M
MM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D017077:Culture Media, Conditioned; D004357:Drug Synergism; D010450:Endopeptidases / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology*; D008970:Molecular Weight; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013002:Somatomedins / Q000502:physiology*; D014132:Trachea / Q000166:cytology* / Q000378:metabolism
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D018971:Insulin-Like Growth Factor Binding Protein 2; D010446:Peptide Fragments; D012333:RNA, Messenger; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D017998:Leukotriene D4; D010450:Endopeptidases; C095329:IGFBP-2 protease