PPARγ in Monocytes: Less Pain, Any Gain?

the myeloid lineage was described earlier, no biological Introduction function for this receptor in these cells has been deAs the population of the U.S. and other industrial counscribed. In the past few months, four papers have pretries ages and gets fatter, there is a more urgent need sented data suggesting that ligand activation of this to understand the molecular basis of obesity and those receptor powerfully regulates several aspects of monocommon and serious medical conditions clearly associcyte biology in ways that offer potential therapeutic ated with obesity: type II diabetes and cardiovascular promise and potential worries about side effects. disease. The cloning and identification of PPARg as a PPARg and Inflammation nuclear receptor that can regulate important facets of Monocytes and macrophages are involved in inflammaenergy balance has offered new opportunities to undertory action through theelaboration of multiple molecules stand and manipulate several key metabolic processes. including nitric oxide (NO) and inflammatory cytokines Ligand activation of PPARg in cultured fibroblasts or such as TNFa and IL-1. The first paper of this series preadipocytes stimulates adipose cell differentiation, in(Ricote et al., 1998) reports that PPARg mRNA is excluding the cessation of cell growth (Spiegelman and pressed at higher levels in peritoneal macrophages elicFlier, 1996, and references therein). While adipose differited with thioglycollate than in monocytes obtained from entiation is also increased by PPARg ligands in vivo, the bone marrow. Ordinarily, when these peritoneal they do not necessarily cause a great increase in total macrophages are treated with interferon g, they respond adipose mass (obesity). Recognition that PPARg is the with an increase in the inducible form of nitric oxide receptor for the antidiabetic thiazolidinedione (TZD) synthase (iNOS) and NO, as well as the secretion of drugs, such as troglitazone (Rezulin), linked this receptor other inflammatory products such as gelatinase B (Gel to glucose homeostasis in rodents and humans (Forman B). Ricote et al. report that when these cells are treated et al., 1995; Kliewer et al., 1995). It is estimated that simultaneously with either of two different ligands for 730,000 Americans currently take this drug to improve PPARg, 15d-PGJ2 or very high concentrations (100 mM) insulin action in diabetes and advanced clinical trials of the TZD BRL49653, the production of iNOS, NO, and are currently underway to assess its activity in other Gel B is reduced. Analysis of the promoters of iNOS insulin-resistant states such as polycystic ovarian synand Gel B have revealed binding sites for AP-1, NF-kB, drome. In addition, clinical trials are underway to assess and STAT1. Using isolated multimerized sites, a TZDthe ability of TZDs to prevent diabetes and to regulate dependent repression of transcription through all of cell growth in cancers of the adipogenic lineage (liposarthese elements was observed. coma) and other, more common cancers as well. A related study was also performed in human monoAlthough adipose tissue has been recognized as a cytes by Jiang et al. (1998). It is well known that exposure principal site of expression of PPARg, it is expressed of monocytes to lipopolysaccharide (LPS) or to tumor at lower levels in many other tissues and cell types and promoters such as PMA potently and rapidly induce may very well play important roles in nonadipose sites. inflammatory cytokines such as TNFa, IL-6, and IL-1B. The ability to study PPARg in different biological conIn this study, a very wide range of ligands, including a texts is enhanced by the availability of several classes TZD (troglitazone), 15d-PGJ2,and certain NSAIDs strongly of ligands. The TZDs are synthetic compounds that are inhibited cytokine production. The NSAIDs are of particvery specific agonists for PPARg (KD 5 30–700 nM) ular interest because it has been observed that certain (Forman et al., 1995; Lehmann et al., 1995). 15-deoxyD compounds such as indomethacin and ibuprofen can prostglandin J2 (15d-PGJ2) is a natural ligand that has have incremental anti-inflammatory actions at concenlower affinity for PPARg than the TZDs (KD 5 2 mM) and trations far above the levels needed to inhibit cyclooxymay not be as selective for this receptor (Forman et al., genase. Interestingly, these PPARg agonists suppressed 1995; Kliewer et al., 1995; Brun et al., 1996). Certain cytokine production elevated by PMA, but not by LPS. polyunsaturated fatty acids such as linoleic acid also This suggests a clear-cut specificity in the inhibitory bind to and activate PPARg, though the affinity here is mechanisms mediated by PPARg. Taken together, these in the 10–20 mM range (Kliewer et al., 1997). In addition, two papers demonstrate that ligands for PPARg were certain nonsteroidal anti-inflammatory drugs (NSAIDs) effective in reducing levels of inflammatory cytokines, like ibuprofen can activate this receptor (Lehmann et as well as downstream markers of inflammation such al., 1997). Although the KD for PPARg is quite high (100 as NO elaborated by monocytic cells. It will be important mM), this receptor may participate in some actions of for the future to try to develop a greater mechanistic the NSAIDs that cannot be ascribed to inhibition of understanding of how PPARg can suppress this broad