IFN, can be blocked by ligands for peroxisome proliferator-activated receptors (PPARs). However, the mechanisms, and even the validity, of this antiinflammatory role for PPARs has recently come under question. The paper by Welch et al.(1) in this issue of PNAS addresses some of these concerns, and suggests that the proposed antiinflammatory effects may result from activation of at least two members of this family of molecules. PPARs represent a subgroup of the nuclear receptor superfamily that contributes to lipid and carbohydrate balance, and hence, homeostatic regulation of energy supplies. They appear to act as lipid sensors and to regulate transcription of lipid metabolizing enzymes, many within the peroxisome (hence their imposing name). The three subtypes of PPAR (, or, and) have different tissue distribution, different (though overlapping) ligand specificity, and mediate their effects by regulating different patterns of gene expression. PPAR is found mainly in heart, liver, and kidney, ie, tissues with high rates of lipid oxidation, regulates fatty acid catabolism, and has been suggested to act as a ‘‘lipostat’’to match lipid delivery to oxidative capacity. PPAR is ubiquitously expressed, but is the least well understood of the group, in terms of either ligands or target genes. By contrast, PPAR is found (and can be up-regulated) in many cell types, but particularly in adipocytes and macrophages. By appropriate induction of gene expression as well as cooperitivity with other nuclear receptors, PPAR has been suggested to play a key role in adipose tissue development and cholesterol import and export (2). It can be activated by thiazolidinedione (TZD) drugs (eg, rosiglitazone), which are used to improve insulin sensitivity in diabetic patients. In addition, over the last 5 years, an antiinflammatory effect has been ascribed to PPAR activation in macrophages resulting from suppression of their production of proinflammatory mediators. Originally, this was shown by experiments in which, for example, induction of inducible NOS (iNOS), cyclooxygenase (COX2), proteases, and inflammatory mediators by LPS or IFN was reduced by ligands of PPAR, including rosiglitazone and 15 deoxy Δ12, 14 prostaglandin J2 (hereafter termed 15PGJ2)(3, 4). The potential antiinflammatory effects of PPAR activation have since received significant attention, not in the least because of the availability, and in some cases antiinflammatory properties, of pharmacologic activating ligands. However, the effects and mechanisms have also become controversial. In particular, there appeared to be a discordance between ligand-binding affinities for the PPAR and antiinflammatory effect as well as a significant lack of understanding as to how the PPAR may be acting, or even whether the PPAR is required for the antiinflammatory effects of the putative activating ligands (5–7).

Previous studies by Chawla et al.(6) had examined responses to PPAR ligands in macrophages derived from PPARJ/J embryonic stem (ES) cells and found that LPS stimulation of proinflammatory genes (iNOS and COX2 for example) were still suppressed. In their own examination of this discrepancy, Welch et al.(1) used a cre–lox system to delete PPAR from macrophages in vivo and also examined the cells for gene expression by microarray techniques. In thioglycollateelicited macrophages, even a relatively high concentration of the PPAR activator rosiglitazone induced increased expression of only a very few genes. Most of these were involved in lipid homeostasis and included the type B scavenger receptor, CD36.