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Received for publication July 15, 2004.
Revised September 4, 2004.
Accepted for publication September 8, 2004.
is not necessary for synthetic PPAR agonist inhibition of iNOS and Nitric Oxide
PPAR
agonists inhibit iNOS, TNF
, and IL-6. Because of these effects, synthetic PPAR agonists, including thiazolidinediones are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPAR agonists range from 10µM - 50µM, while their binding affinity for PPAR is in the nanomolar range. The specificity of synthetic PPAR agonists for PPAR at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPAR is not necessary for the inhibition of iNOS by synthetic PPAR agonists. RAW 264.7 macrophages possess little PPAR, yet LPS/IFN induced iNOS was inhibited by synthetic PPAR agonists at 20µM. Endogenous PPAR was inhibited by the transfection of a dominant-negative PPAR construct into murine mesangial cells. In the transfected cells, synthetic PPAR agonists inhibited iNOS production at 10µM, similar to non-transfected cells. Using cells from PPAR cre/lox conditional knockout mice, baseline and LPS/IFN induced NO levels were higher in macrophages lacking PPAR versus controls. However, synthetic PPAR agonists inhibited iNOS at 10µM in the PPAR deficient cells, similar to macrophages from wild-type mice. These results indicate that PPAR is not necessary for inhibition of iNOS expression by synthetic PPAR? agonists at concentrations over 10µM. However, intrinsic PPAR function, in the absence of synthetic agonists, may play a role in inflammatory modulation.
Key words:
Inflammation, NO, PPAR, Prostaglandin, TZD, iNOS
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