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B-Dependent Signaling Pathway That Is Only Partially Sensitive to Dexamethasone1
Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104
Although the precise mechanisms by which steroids mediate their
therapeutic effects remain unknown, steroids have been reported to
abrogate cytokine-induced activation of the transcription factor
NF-
B. In some cell types, NF-B activation is necessary to
regulate cytokine-mediated cellular functions. However, compelling
evidence suggests that the steroid inhibition of NF-B is complex and
cell specific. Using EMSA, we show that stimulation with TNF-
or
IL-1ß induces NF-B DNA-binding activity in human airway smooth
muscle cells. TNF- and IL-1ß also increased luciferase activity in
airway smooth muscle cells transfected with a reporter plasmid
containing B enhancer elements. Cytokines activated NF-B by
rapidly degrading its cytosolic inhibitor IB, which was then
regenerated after 60 min. Cytokine-mediated IB reappearance was
completely blocked by the protein synthesis inhibitor cycloheximide.
Inhibition of cytokine-mediated IB proteolysis using the protease
inhibitors N-tosyl-L-phenylalanine
chloromethyl ketone and
N-acetyl-L-leucinyl-L-leucinyl-norleucinal
also inhibited cytokine-mediated early expression of ICAM-1. Although
dexamethasone partially inhibited IL-1ß- and TNF--induced
up-regulation of ICAM-1 at 4 h, dexamethasone had no effect on
cytokine-induced ICAM-1 expression at 18–24 h. In addition, neither
cytokine-induced degradation or resynthesis of IB nor NF-B
DNA-binding activity were affected by dexamethasone. In cells
transfected with the luciferase reporter, dexamethasone did not affect
TNF--induced NF-B-dependent transcription. Interestingly,
cytokine-mediated expression of cyclooxygenase-2 was completely
abrogated by dexamethasone at 6 h. Together, these data
demonstrate that cytokine-mediated NF-B activation and ICAM-1
expression involve activation of a steroid-insensitive
pathway.
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