Pioglitazone Acts Synergistically with IL‐1 to Activate Expression of Matrix Metalloproteinase‐3 (MMP‐3) in Human Gingival Fibroblasts (HGF)

Previously we showed that IL‐4 inhibits the IL‐1 induction of MMP‐3 in HGF. The present study evaluates the hypothesis that the mechanism of IL‐4 inhibition involves activation of peroxisome proliferator‐activated receptor‐£^ƒnƒvPPAR‐£^ƒw via increased lipoxygenase activity, and that a putative composite PPRE/activator protein‐1 (AP‐1) binding site in the MMP‐3 promoter is involved.ƒnƒn Results of real‐time PCR experiments show that both inhibition of lipoxygenase enzymes with nordihydroguaiaretic acid (NDGA) and activation of PPAR‐£^ with pioglitazone (1 ¡V 30 uM) synergistically activate IL‐1‐induced expression of MMP‐3. IL‐4 was still able to inhibit MMP‐3 expression in the presence of IL‐1 and NDGA, suggesting IL‐4 and NDGA work through separate pathways. Furthermore, IL‐1 induced binding to the putative composite PPRE/AP‐1 site was not changed by the presence of pioglitazone. Additional experiments will address whether pioglitazone and/or NDGA affect the ability of nuclear factor‐£eB (NF‐£eB) to repress MMP‐3 expression through a polymorphic binding site in the MMP‐3 promoter. This work is supported by grant R15DE16277 from the NIDCR to R.C. Borghaei, and a Supplement to Promote Diversity in Health‐related Research to D. Stewart.