Coactivator function of RIP140 for NFκB/RelA-dependent cytokine gene expression

Abstract

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, ...

Transcriptional co-factors and hepatic energy metabolism

“…Indeed, in gene-specific contexts, RIP140 serves as a co-activator for NFkappaB, a master transcriptional regulator of inflammation. Intriguingly, RIP140's co-activator function in this setting relied on direct protein-protein interactions with the NFkappaB subunit RelA and histone acetylase CBP [164]. Intriguingly, RIP140 gene expression was found to be induced in livers of septic and tumor-bearing mice.…”

Complex Formation and Function of Estrogen Receptor α in Transcription Requires RIP140

“…Recently, we found RIP140 to be required for normal mammary gland development, where it functions as an essential component in estrogen signaling (7). RIP140 has a dual role as a transcriptional regulator, acting as both a corepressor for catabolic genes in metabolic tissue (3,8) and a coactivator for inflammatory genes (9). RIP140 functions as a coactivator for ERa-responsive genes in mammary gland formation (7).…”

The metabolic coregulator RIP140: an update

“…For example, RIP140 was shown to activate inflammatory gene expression in macrophages (37), triglyceride synthesis in the liver (14), and, more recently, amphiregulin expression in the ovary to promote ovulation (23). In this review, we focus on recent advances in our understanding of the function of RIP140 as a regulator of energy homeostasis.…”