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B and Mitogen-Activated Protein Kinase Signaling Pathways in IL-1ß-Mediated Induction of 
-PDGF Receptor Expression in Rat Pulmonary Myofibroblasts
Airway Inflammation Section, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
Induction of the 
-platelet-derived growth factor receptor
(PDGF-R) by IL-1ß in lung myofibroblasts enhances mitogenic and
chemotactic responses to PDGF, and this could be a mechanism of
myofibroblast hyperplasia during lung fibrogenesis. Since the
regulation of many genes by IL-1ß involves activation of NF-
B and
mitogen-activated protein (MAP) kinases, we examined these signaling
pathways in the control of PDGF-R expression by IL-1ß in cultured
rat lung myofibroblasts. Treatment of cells with pyrrolidine
dithiocarbamate (PDTC), an antioxidant that inhibits NF-B
activation, completely blocked PDGF-R up-regulation by IL-1ß as
assayed by [125I]PDGF-AA binding and PDGF-R mRNA
expression, suggesting a role for NF-B. However, while IL-1ß and
TNF- both induced nuclear binding of the Rel proteins p50 and p65 to
an NF-B consensus oligonucleotide in gel shift assays and caused
transient degradation of inhibitor of NF-B- (IB-) in the
cytoplasm of myofibroblasts, only IL-1ß up-regulated PDGF-R. These
results suggest that NF-B activation alone is not sufficient for
up-regulation of PDGF-R. An investigation of MAP kinase signaling
pathways revealed that IL-1ß or PDTC activated extracellular
signal-regulated kinase-2 (ERK-2) and c-jun
NH2 terminal kinase-1 (JNK-1) phosphorylation of
PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells
with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked
IL-1ß-induced activation of ERK-2 by more than 90% but enhanced
IL-1ß-stimulated induction of PDGF-R expression fourfold. Taken
together, these data suggest that IL-1ß activates both positive and
negative signaling pathways that control the expression of PDGF-R.
IL-1ß appears to mediate its negative effects on PDGF-R expression
via MAP kinase activation, while the factor(s) that mediate induction
of PDGF-R remain to be elucidated.
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