Inflammatory responses represent a hallmark of numerous pathologies including sepsis, bacterial infection, insulin resistance, and malign obesity. Here we describe an unexpected coactivator function for the nuclear receptor interacting protein 140 (RIP140) for nuclear factor B (NFB), a master transcriptional regulator of inflammation in multiple tissues. Previous work has shown that IntroductionMetabolic diseases, such as insulin resistance, obesity, and atherosclerosis, have recently been recognized as low-grade, subacute inflammatory conditions, contributing to the development of type II diabetes and cardiovascular failure. 1 Similar to acute inflammation, all of these conditions are characterized by elevated levels of proinflammatory cytokines such as interleukin-1␤ (IL-1␤) and IL-6, and tumor necrosis factor ␣ (TNF␣). 2,3 Toward this end, levels of IL-6, IL-1␤, and TNF␣ are elevated in obese patients and mouse models of insulin resistance and obesity. [2][3][4] In this respect, ablation of the TNF␣ gene or of its receptor renders mice resistant to the development of insulin resistance and associated metabolic disorders. 5,6 A common polymorphism has been identified in the IL-6 receptor gene that is associated with energy intake and obesity in humans, 7 underlining the critical impact of cytokine signaling for metabolic diseases.The inflammatory response emerging in the presence of insulin resistance and obesity seems to reside predominantly in adipose tissue. 1,8 Indeed, transgenic overexpression of monocyte chemotactic protein 1 (MCP1) in adipose tissue results in enhanced macrophage infiltration, inflammation, and insulin resistance. 9,10 On the other hand, impairment of macrophage migration into adipose tissue by genetic knockout of the MCP1 receptor chemotactic cytokine receptor 2 (CCR2) has been found to substantially improve tissue inflammation and insulin sensitivity. 10,11 Importantly, macrophages have recently been shown to accumulate under obese conditions in adipose tissue of both mice and humans. 12,13 Resident macrophages in adipose tissue, therefore, seem to be in large part responsible for the cytokine release of this tissue and the systemic inflammation associated with obesity. 12,14 These studies highlighted the importance of adipose tissue as a key site for the interaction of metabolic cells with effectors of the immune system, specifically macrophages, to control systemic energy homeostasis and to trigger metabolic dysfunction under pathophysiologic conditions. 8 Consequently, not only adipose tissue quantity but also quality, as exemplified by its macrophage content and inflammatory status, seems to represent a critical determinant for the onset of insulin resistance and other components of the metabolic syndrome. 8,15 In this respect, the cytokine release from macrophages in response to external signals is largely determined by transcriptional mechanisms. A number of transcriptional regulators have been identified as critical checkpoints for the proinflammatory response of macrophages, ...

Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)␥ is a transcription factor known to have antidiabetogenic and immune effects, and PPAR␥ forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPAR␥-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 ؎ 5.8 (controls) vs. 8.1 ؎ 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 ؎ 1.8 (controls) vs. 2.6 ؎ 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-␤1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPAR␥ activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPAR␥-dependent manner. The combination of PPAR␥-and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPAR␥ activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/

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