Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Inhibit IL-6 or TNF-α Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo

Abstract

We have investigated the potential use of peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ agonists. Although 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) at micromolar concentrations significantly inhibited the production of TNF-α and IL-6, four other high affinity PPARγ 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 PPARγ or when the murine macrophage cell line RAW 264.7 was used. Furthermore, saturating concentrations of a potent PPARγ ligand not only failed to block cytokine production, but also were unable to block the inhibitory activity of 15d-PGJ2. Thus, activation of PPARγ 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 PPARγ-independent mechanism. To examine the anti-inflammatory activity of PPARγ 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-α 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 PPARγ in leukocytes will not be useful for the treatment of acute inflammation.

Differential Regulation of Chemokine Gene Expression by 15-Deoxy-Δ12,1412,14 Prostaglandin J2

“…Earlier studies have demonstrated that 15d-PGJ 2 could suppress expression of several genes in PMA-activated monocytes/ macrophages, including those coding for inducible NO synthase, TNF-␣, IL-1␣, IL-6, and gelatinase B/matrix metalloproteinase-9 (7,8,12). However, other studies showed that activation of PPAR␥ did not inhibit the production of proinflammatory cytokines induced by LPS stimulation (13). Therefore, whether 15d-PGJ 2 and its synthetic analogs can be safely used as antiinflammatory agents remains elusive.…”

“…These observations raise the possibility that 15d-PGJ 2 may be a potential therapeutic compound for treatment of inflammatory diseases. However, other studies have failed to observe an inhibitory effect of 15d-PGJ 2 on induced expression of TNF-␣ and IL-6 in freshly prepared human monocytes/macrophages (13). Thus, whether 15d-PGJ 2 will be of therapeutic value as an antiinflammatory agent remains controversial.…”

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

“…inflammatory effects (Thieringer et al, 2000;Guyton et al, 2001;Moore et al, 2001b;Fu et al, 2002). Thus, PPARs have been shown to have in vivo relevance with inflammatory processes, and that is the reason why the mechanisms underlying these effects are highly interesting to clarify.…”

Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

“…Previous studies have demonstrated that 15deoxy-PGJ 2 was more effective than synthetic PPAR␥ ligands in reducing the expression of iNOS and cytokines by monocytes (27). It has been shown that high concentrations of thiazolidinedione antidiabetic drugs are re-quired to obtain antiinflammatory activities.…”