Rat renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin 1␤ (IL-1␤). We tested whether ligands of the peroxisome proliferator-activated receptor (PPAR␣) could influence the cytokineinduced expression of MMP-9. Different PPAR␣ agonists dose-dependently inhibited the IL-1␤-triggered increase in gelatinolytic activity mainly by decreasing the MMP-9 steady-state mRNA levels. PPAR␣ agonists on their own had no effects on MMP-9 mRNA levels and gelatinolytic activity. Surprisingly, the reduction of MMP-9 mRNA levels by PPAR␣ activators contrasted with an amplification of cytokine-mediated MMP-9 gene promoter activity and mRNA expression. The potentiation of MMP-9 promoter activity functionally depends on an upstream peroxisome proliferator-responsive element-like binding site, which displayed an increased DNA binding of a PPAR␣ immunopositive complex. In contrast, the IL-1␤-induced DNA-binding of nuclear factor B was significantly impaired by PPAR␣ agonists. Most interestingly, in the presence of an inducible nitric-oxide synthase (iNOS) inhibitor, the PPAR␣-mediated suppression switched to a strong amplification of IL-1␤-triggered MMP-9 mRNA expression. Concomitantly, activators of PPAR␣ potentiated the cytokineinduced iNOS expression. Using actinomycin D, we found that NO, but not PPAR␣ activators, strongly reduced the stability of MMP-9 mRNA. In contrast, the stability of MMP-9 protein was not affected by PPAR␣ activators. In summary, our data suggest that the inhibitory effects of PPAR␣ agonists on cytokine-induced MMP-9 expression are indirect and primarily due to a superinduction of iNOS with high levels of NO reducing the half-life of MMP-9 mRNA.Dysregulation of extracellular matrix turnover is an important feature of glomerular inflammatory processes and may result in the loss of the mechanical and functional integrity of the glomerulus (1-3). Physiologically, the balance between synthesis and degradation of matrix proteins is guaranteed by the action of a family of zinc-dependent, neutral proteinases designated matrix metalloproteases (MMPs).1 A tight regulation of these proteases is accomplished by different mechanisms, including the regulation of gene expression, the processing of the inactive zymogenes by other proteases, and finally, the inhibition of the active enzymes by the action of endogenous inhibitors of MMPs, the TIMPs (for review, see Ref. 4). Cultured mesangial cells (MC) respond to proinflammatory cytokines such as tumor necrosis factor or interleukin-1␤ (IL-1␤) with the production of several MMPs, including MMP-9 (gelatinase-B), mainly due to an increase in gene transcription (5, 6). The transcriptional regulation of the rat MMP-9 gene by proinflammatory cytokines is localized to a 0.7-kb region upstream from the transcriptional start site and critically depends on the binding sites for activator protein-1 (AP-1) and nuclear factor B (NF-B) transcription factors, respectively (5, 7). Besides MMP-9, MC under inf...