Peroxisome proliferator-activated receptor ? activators inhibit interleukin-1?-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes
Open Access
- 19 March 2001
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 44 (3) , 595-607
- https://doi.org/10.1002/1529-0131(200103)44:3<595::aid-anr108>3.0.co;2-8
Abstract
Objective To determine the effects of peroxisome proliferator–activated receptor γ (PPARγ) agonists on interleukin‐1 (IL‐1) induction of nitric oxide (NO) and matrix metalloproteinase 13 (MMP‐13) in human chondrocytes. Methods PPARγ expression and synthesis in human chondrocytes were determined by reverse transcriptase–polymerase chain reaction (RT‐PCR) and immunohistochemistry, respectively. Chondrocytes were cultured with IL‐1β, tumor necrosis factor α (TNFα), and IL‐17 in the presence or absence of PPARγ agonists, and NO and MMP‐13 synthesis and expression levels were measured. Transient transfection experiments were performed with the 7‐kb inducible NO synthase (iNOS) and 1.6‐kb MMP‐13 human promoters, as well as with the PPARγ expression vector and the activator protein 1 (AP‐1) and nuclear factor κB (NF‐κB) reporter constructs. Results RT‐PCR and immunohistochemical analysis revealed that human chondrocytes expressed and produced PPARγ. Treatment of chondrocytes with PPARγ ligands BRL 49653 and 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), but not with PPARα ligand Wy 14643, decreased IL‐1β–induced NO and MMP‐13 production in a dose‐dependent manner. In addition, both iNOS and MMP‐13 messenger RNA were inhibited in the presence of 15d‐PGJ2. The inhibitory effect of PPARγ activation was not restricted to IL‐1β, since TNFα‐ and IL‐17–induced NO and MMP‐13 production were also inhibited by 15d‐PGJ2. In transient transfection experiments, we showed that a constitutively active form of mitogen‐activated protein kinase kinase kinase 1 (ΔMEKK‐1) induced the MMP‐13 and iNOS human promoter activity. This process was reduced by 15d‐PGJ2 and further inhibited by cotransfection with a PPARγ expression vector. Similarly, in a PPARγ‐dependent manner, 15d‐PGJ2 inhibited ΔMEKK‐1–induced AP‐1– and NF‐κB–luciferase reporter plasmid activation. Conclusion The findings of this study demonstrate that PPARγ agonists inhibit IL‐1β induction of both NO and MMP‐13 in human chondrocytes. The inhibition occurs at least at the transcriptional level through a PPARγ‐dependent pathway, probably by interfering with the activation of AP‐1 and NF‐κB.Keywords
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