Abstract
BackgroundInterleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-γ (PPARγ) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARγ by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARγ may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters. The objective of this study was to determine whether the suppressive effects of IL-4 on the IL-1 induced expression of MMP-3 involve activation of lipoxygenase and/or PPARγ.ResultsWestern blotting revealed the presence of PPARγ in nuclear extract of HGF. IL-1 induced binding of nuclear extract to the putative composite PPRE/AP-1 site was diminished in the presence of pioglitazone, but there was no evidence of any change in the composition of the retarded complexes, and no evidence of PPARγ binding to this site. Nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase inhibitor, and MK886, a specific inhibitor of 5-lipoxygenase, induced MMP-3 expression synergistically with IL-1. However IL-4 was still able to inhibit MMP-3 expression in the presence of NDGA or MK886 and IL-1. Activation of PPARγ with pioglitazone not only failed to inhibit IL-1 induced expression of MMP-3 mRNA, but rather super-induced MMP-3 in the presence of IL-1. PPARγ antagonist GW9662 failed to abolish the suppressive effects of IL-4. Another PPARγ activator, 15-deoxy-Delta12,14prostaglandin J2 (15dPGJ2), also super-induced MMP-3 mRNA, and this was due at least in part to increased transcription.ConclusionIL-4 suppression of IL-1-induced MMP-3 expression in HGF is independent of lipoxygenase activity and activation of PPARγ. Super-induction of MMP-3 by pioglitazone may have important implications for patients using pioglitazone to treat type II diabetes in the presence of chronic inflammation.
Highlights
Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined
In order to demonstrate the presence of peroxisome proliferatoractivated receptor-γ (PPARγ) in human gingival fibroblasts (HGF), nuclear extract were isolated from control cultures and from HGF cultures treated for 24 hours in the presence of IL-1 (10 ng/ml) and/or IL-4 (10 ng/ml)
IL-4 has been shown to inhibit the IL-1 induction of matrix metalloproteinases (MMPs)-3 expression in human conjunctival fibroblasts [30], skin fibroblasts [31] and articular chondrocytes [32,33], as well as in synovial fibroblast cultures established from patients with osteoarthritis [34] and gingival fibroblast (HGF) cultures established from patients with periodontitis [35]
Summary
Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Studies of the effects of a promoter polymorphism that affects protein expression has shown that individuals with the high expressing 5A/5A genotype are at increased risk for aneurysms and myocardial infarctions [13,14,15], while those with the lower expressing 6A/6A genotype show a faster progression of atherosclerosis [15,16]. Taken together, these studies suggest that regulation of MMP-3 levels is important for the maintenance of health, and that either too much or too little can have detrimental effects
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