Leukotriene d4 induces mmp-1 which functions as an igf binding
protein protease in human airway smooth muscle cells.
Rajah, Roopmathy, Steven E. Nunn, David J. Herrick, Michael M.
Grunstein, and Pinchas Cohen.
Divisions of Endocrinology, and Pulmonary Medicine, Joseph Stokes,
Jr. Research Institute, Children's Hospital of Philadelphia,
University of Pennsylvania School of Medicine
APStracts 3:0159L, 1996.
We have previously demonstrated that the asthma-associated pro
-inflammatory eicosanoid, leukotriene D4 (LTD4), is co-mitogenic with
insulin-like growth factors (IGFs) 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
(IGFBPs). 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 IGFBPs (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-IGFBPs
demonstrated that an IGFBP protease was induced in the ASM cells in
response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti
-MMP-1 antibodies demonstrated a dose-dependent reduction of IGFBP
proteolysis. Tissue inhibitor of metalloproteinase-1 and Batimastat
(synthetic) inhibited proteolysis of IGFBPs. 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 which 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.
Received 27 March 1996; accepted in final form 6 August 1996.
APS Manuscript Number L102-6.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 7 October 1996