INTERLEUKIN-13 INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION INHUMAN MESANGIAL CELLS

The synthesis of nitric oxide in inflammatory situations requires the expression of an inducible isoform of nitric oxide synthase (iNOS). Hu man mesangial cells (HMC) express an iNOS enzyme after exposure to mul tiple co-stimuli. In this study we have observed that while tumour nec rosis factor-alpha, interleukin (IL)-1 beta, interferon-gamma and bact erial lipopolysaccharide (LPS) were unable to significantly induce NO synthesis when used alone, they induced an evident stimulation of NO s ynthesis when used in various combinations. A mixture of the three cyt okines (CM) and LPS resulted in a 10-15-fold stimulation of NO synthes is over control values which started to be significant after 16 h. The addition of IL-13, a cytokine with anti-inflammatory properties, inhi bited CM/LPS-induced NO synthesis in a concentration-dependent manner. A marked inhibitory effect (60-65%) could be observed when HMC were t reated with IL-13 (10 ng/ml) 24 h before, at the same time as, or even 4 h after the addition of CM/LPS. This inhibitory effect was still si gnificant (25%) when IL-13 was added 16 h after CM/LPS. Northern analy sis showed that IL-13-mediated iNOS inhibition was closely correlated with the suppression of iNOS mRNA expression. These results identify I L-13 as a powerful regulatory tool for the inhibition of NO synthesis in human cells, a property which may be pathophysiologically relevant in NO-related inflammatory processes.