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*
Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; and
Abteilung Pharmakologie, Biozentrum, Universität Basel, Basel, Switzerland
Expression of the inducible nitric oxide synthase (iNOS) gene in
rat mesangial cells is differentially triggered by IL-1ß and cAMP
predominantly at the transcriptional level. The 5'-flanking region of
the rat iNOS gene contains several binding sites for transcription
factors potentially involved in cytokine and cAMP signaling such as
nuclear factor-
B/Rel, CCAAT/enhancer-binding protein (C/EBP), and
cyclic AMP-responsive element-binding protein/ATF. We tested promoter
activities of serial and site-directed deletion mutants of
iNOS-chloramphenicol acetyltransferase reporter genes after transient
transfection and stimulation of mesangial cells. A region between bp
-277 and -111 bearing a CCAAT/enhancer-binding protein-response
element was found to be critical for cAMP-mediated gene induction but
dispensable for IL-1ß inducibility. Moreover, a minimal promoter
ranging from the transcriptional start site up to -111 containing a
B site is sufficient to confer IL-1ß-mediated iNOS promoter
activation. Consistent with these findings, an electrophoretic mobility
shift assay shows the appearance of an IL-1ß-inducible nuclear
factor-B p50/p65 heterodimeric complex. Using probes containing
C/EBP-binding sites from the iNOS gene revealed further binding of
different complexes, all of which were strongly inducible by cAMP and
to a lower extent also by IL-1ß. Abs against cyclic AMP-responsive
element-binding protein, C/EBPß, and C/EBP
were able to partially
supershift single complexes, suggesting the participation of these
transcription factors in the regulation of iNOS gene expression by cAMP
and IL-1ß. Finally, we show that both cAMP and IL-1ß strongly
induce steady-state levels of C/EBPß and C/EBP mRNA levels. These
data demonstrate that IL-1ß and cAMP use distinct as well as
partially overlapping sets of transcriptional activators to modulate
iNOS gene expression in rat mesangial cells.
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