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Does Not Inhibit IL-6 or TNF-
Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo
Departments of
*
Endocrinology and Chemical Biology,
Laboratory Animal Resources, and
Molecular Endocrinology, Merck Research Laboratories, Rahway, NJ 07065
We have investigated the potential use of peroxisome
proliferator-activated receptor 
(PPAR) agonists as
anti-inflammatory agents in cell-based assays and in a mouse model
of endotoxemia. Human peripheral blood monocytes were treated with LPS
or PMA and a variety of PPAR agonists. Although
15-deoxy-
12,14-prostaglandin J2
(15d-PGJ2) at micromolar concentrations significantly
inhibited the production of TNF-
and IL-6, four other high affinity
PPAR ligands failed to affect cytokine production. Similar results
were obtained when the monocytes were allowed to differentiate in
culture into macrophages that expressed significantly higher levels of
PPAR or when the murine macrophage cell line RAW 264.7 was used.
Furthermore, saturating concentrations of a potent PPAR ligand not
only failed to block cytokine production, but also were unable to block
the inhibitory activity of 15d-PGJ2. Thus, activation of
PPAR does not appear to inhibit the production of cytokines by
either monocytes or macrophages, and the inhibitory effect observed
with 15d-PGJ2 is most likely mediated by a
PPAR-independent mechanism. To examine the anti-inflammatory
activity of PPAR agonists in vivo, db/db mice were
treated with a potent thiazolidinedione that lowered their elevated
blood glucose and triglyceride levels as expected. When
thiazolidinedione-treated mice were challenged with LPS, they displayed
no suppression of cytokine production. Rather, their blood levels of
TNF- and IL-6 were elevated beyond the levels observed in control
db/db mice challenged with LPS. Comparable results were
obtained with the corresponding lean mice. Our data suggest that
compounds capable of activating PPAR in leukocytes will not be
useful for the treatment of acute inflammation.
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