: counter-regulatory activity by IFN-
Neurocrine Biosciences, Inc., San Diego, California
Correspondence: Drs. David Alleva and Paul Crowe, Neurocrine Biosciences, Inc., 10555 Science Center Dr., San Diego, CA 92121-1102. E-mail: dalleva{at}neurocrine.com and pcrowe{at}neurocrine.com
The prostaglandin, 15-deoxy 
12,14-prostaglandin J2 (15d-PGJ2)1, and thiazolidinediones are ligands for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)-
, which mediates anti-inflammatory activity by suppressing murine macrophage (M
) production of the inflammatory mediator, nitric oxide (NO). Here, we elucidated this anti-inflammatory activity further by investigating whether PPAR- ligands regulated a panel of proinflammatory and anti-inflammatory cytokines produced by primary inflammatory murine M (thioglycollate-elicited peritoneal exudate M; PEM). Thiazolidinediones and 15d-PGJ2 suppressed lipopolysaccharide (LPS)-induced PEM production of NO and IL-12(p40) to a greater extent than IL-6 and TNF-
production. Whereas 15d-PGJ2 showed the greatest extent of suppression of proinflammatory mediator production, the thiazolidinedione, BRL49653, was the most potent compound studied. Surprisingly, treatment with the M-activation cytokine, IFN-, prevented PPAR- ligands from suppressing the proinflammatory cytokines completely and reduced their suppression of NO production substantially, demonstrating that activation conditions affect PPAR--mediated, anti-inflammatory activity. Western analysis demonstrated that the antagonistic activity of IFN- did not involve modulation of PPAR- expression but showed that IFN- interfered with PPAR- ligand regulation of p42/p44 MAP kinase activation and the cytosolic disappearance of NF-
B upon LPS stimulation. Finally, we showed that PPAR- ligands did not substantially modulate production of the anti-inflammatory cytokine, IL-10, and that antibody-mediated neutralization of IL-10 did not prevent the ligands from suppressing proinflammatory mediator production. In contrast to studies with noninflammatory human monocytes and M, our results demonstrate that primary murine inflammatory M are extremely sensitive to the anti-inflammatory activity of PPAR- ligands. These results suggest that drugs such as thiazolidinediones may be most effective in suppressing M activity early (i.e., in the absence of lymphocyte-derived IFN-) in the inflammatory process.
Key Words: prostaglandin • thiazolidinedione • nuclear receptor • nitric oxide
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