Suppression of macrophage inflammatory responses by PPARs

The proinflammatory response of macrophages to stimuli, such as lipopolysaccharide (LPS) or IFNγ, 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 (α, β or δ, and γ) have different tissue distribution, different (though overlapping) ligand specificity, and mediate their effects by regulating different patterns of gene expression. PPARα is found mainly in heart, liver, and kidney, i.e., 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. PPARδ is ubiquitously expressed, but is the least well understood of the group, in terms of either ligands or target genes. By contrast, PPARγ 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, PPARγ 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 (e.g., 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 …