Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo
R. Thieringer et al., Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo, J IMMUNOL, 164(2), 2000, pp. 1046-1054
We have investigated the potential use of peroxisome proliferator-activated
receptor gamma (PPAR gamma) agonists as anti-inflammatory agents in cell-b
ased assays and in a mouse model of endotoxemia, Human peripheral blood mon
ocytes were treated with LPS or PMA and a variety of PPAR gamma agonists, A
lthough 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) at micromolar
concentrations significantly inhibited the production of TNF-alpha and IL-
6, four other high affinity PPAR gamma ligands failed to affect cytokine pr
oduction. Similar results were obtained when the monocytes were allowed to
differentiate in culture into macrophages that expressed significantly high
er levels of PPAR gamma or when the murine macrophage cell line RAW 264.7 w
as used. Furthermore, saturating concentrations of a potent PPAR gamma liga
nd not only failed to black cytokine production, but also were unable to bl
ock the inhibitory activity of 15d-PGJ(2), Thus, activation of PPAR gamma d
oes not appear to inhibit the production of cytokines by either monocytes o
r macrophages, and the inhibitory effect observed with 15d-PGJ(2) is most l
ikely mediated by a PPAR gamma-independent mechanism, To examine the anti-i
nflammatory activity of PPAR gamma agonists in vivo, db/db mice were treate
d with a potent thiazolidinedione that lowered their elevated blood glucose
and triglyceride levels as expected. When thiazolidinedione-treated mice w
ere challenged with LPS, they displayed no suppression of cytokine producti
on. Rather, their blood levels of TNF-alpha and IL-6 were elevated beyond t
he levels observed in control db/db mice challenged with LPS. Comparable re
sults were obtained with the corresponding lean mice. Our data suggest that
compounds capable of activating PPAR gamma in leukocytes will not be usefu
l for the treatment of acute inflammation.