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Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Madrid, and Instituto "Reina Sofía" de Investigaciones Nefrológicas, CSIC, 28006 Madrid, Spain
Nitric oxide (NO) and cGMP may exert positive or negative
effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1
plus tumor necrosis factor (TNF)-
reduced iNOS levels, while
NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS
protein and mRNA levels. This suggests that NO may contribute both to
iNOS induction and downregulation. Soluble guanylyl cyclase (sGC)
activation may be involved in these effects. Inhibition of sGC
attenuated IL-1/TNF--elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of
transcription unveiled a negative posttranscriptional modulation of the
iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
inflammatory mediators; human mesangial cells; mRNA stability; nitric oxide; inducible nitric oxide synthase; guanosine 3',5'-cyclic monophosphate
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