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Macrophages and related cells, such as osteoclasts, microglia and Kupffer cells, play diverse roles in host defense and the maintenance of homeostatis (Gordon 1995). Based on their ability to promote inflammatory processes, inappropriate macrophage function also contributes to numerous pathological processes, including the development of atherosclerosis, rheumatoid arthritis and inflammatory bowel disease (Mahida 1995, Ross 1999, Shapiro 1999). Pharmacological modulation of macrophage gene expression therefore represents an important strategy for prevention and treatment. Members of the nuclear receptor superfamily of ligand-dependent transcription factors are attractive targets for development of novel antiinflammatory pharmaceuticals based on the proven antiinflammatory activities of glucocorticoids (McKay & Cidlowski 1999). The use of glucocorticoids ultimately becomes limiting in chronic forms of inflammation, however, due to the development of severe side-effects, that include insulin resistance, obesity and hypertension. Several lines of evidence suggest that the antiinflammatory effects of glucocorticoids primarily result from glucocorticoid receptor-dependent repression of transcription factors such as nuclear factor kappa B, while side-effects primarily result from the activation of direct target genes (McKay & Cidlowski 1999). At least two general strategies can be considered for minimizing unwanted side-effects and maximizing the therapeutic potential of nuclear receptors as targets of antiinflammatory drug development. To the extent that transrepressive activities of the glucocorticoid receptor are shared by other members of the nuclear receptor superfamily, anti-inflammatory drugs might be based on related nuclear receptors, such as peroxisome proliferatoractivated receptors (PPARs), that have a more benign pattern of side-effects when bound to activating ligands. A second strategy is to develop structurally distinct ligands for the glucocorticoid receptor, or other nuclear receptors that exert selective effects on receptor function (Vayssière et al. 1997). This possibility has been most clearly demonstrated in the case of the estrogen receptor. Selective estrogen receptor modulators have been identified that exert proestrogenic effects in some tissues and antiestrogenic effects in others (Dhingra 1999, Levenson 1999). Here, I describe studies of PPARthat suggest it may serve as a target for therapy of chronic inflammatory diseases and atherosclerosis.

Potential roles of the peroxisome proliferator-activated receptor-gamma in macrophage biology and atherosclerosis