Transcription factor cross-talk: the estrogen receptor and NF-κB

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The NF-κB family of transcription factors regulates many genes that are essential primarily for the development, maintenance and function of the innate and adaptive immune systems. Thus, aberrant activity of the nuclear factor NF-κB has a role in many pathological conditions with inflammatory and autoimmune components. Estrogen receptors (ERs) are transcription factors that mediate the biological responses to the sex hormone estrogen and are essential for reproduction and for functions of the cardiovascular, skeletal and nervous systems. Recent studies have demonstrated molecular cross-talk between these families of transcription factors in which the ER mediates inhibition of NF-κB activity at several levels. Such cross-talk between these important regulators of the endocrine and immune systems might be exploited for the treatment of cancer and inflammatory and autoimmune diseases.

Introduction

The mutually antagonistic cross-talk between the NF-κB and ER signaling pathways has been the subject of numerous studies. This cross-talk is particularly relevant in bone physiology, where members of the NF-κB family function to promote bone resorption through the regulation of cytokines such as interleukein-6 (IL-6) [1] and estrogen acts to inhibit this process [2]. In addition, the anti-inflammatory functions of the ER in various animal models of disease and human disorders 2, 3, 4 might be explained, in part, by inhibition of the pro-inflammatory activities of NF-κB [5].

As we describe in this review, the molecular mechanisms and physiological relevance of cross-talk between the ER and NF-κB are now emerging and might have relevance for the treatment of some human diseases.

Section snippets

The NF-κB pathway

The NF-κB family of transcription factors controls various aspects of the immune and skeletal systems, as well as inflammatory responses, and chronic NF-κB activity has been implicated in various diseases including arthritis, diabetes, atherosclerosis, Alzheimer's disease and several cancers 6, 7. NF-κB transcription factors are related through an amino (N)-terminal Rel homology domain (RHD) of about 300 amino acids that contains sequences important for DNA binding, dimerization, inhibitor

The ER pathway

Estrogens (principally 17-β-estradiol) have important roles both in reproduction and in the skeletal, cardiovascular and central nervous systems. Along with estrogen, selective ER modulators (SERMs) such as tamoxifen are widely used in the clinic. Estrogen and SERMs exert their effects through two structurally related, nuclear receptor transcription factors, ERα and ERβ 10, 11, 12. The ERs form homo- and heterodimers. Both ERs contain several independent domains, including a DNA-binding domain

Molecular mechanisms of inhibition of NF-κB by the ER

In κB site-dependent reporter gene assays, ERα has been shown to inhibit NF-κB activity in an estrogen-dependent manner at nanomolar concentrations of estrogen in various cell lines, including U2-OS [18], F9 [19], HeLa 20, 21, 293 [22], U937 [23], HepG2 [24] and MCF-7 [25] cells. Many groups have also shown that ERβ has an inhibitory effect on NF-κB activity 20, 21, 23, 26, 27.

Deletion analysis studies have shown that inhibition of NF-κB activity by ERα requires the LBD, the DBD and the D

The ER, NF-κB and breast cancer

Both the ER and NF-κB pathways have been implicated in breast cancer. Estrogen promotes the growth of some breast cancers; consequently, anti-estrogens can slow the growth of such tumors [12]. The malignant progression of some breast cancers, however, is coincident with a shift from estrogen dependence to estrogen independence and, notably, this shift also coincides with an increase in both NF-κB activity 31, 39 and the expression of some NF-κB target genes such as IL8 [50].

Several additional

Potential ER–NF-κB cross-talk in inflammation and autoimmunity

There are numerous inflammatory and autoimmune diseases in which NF-κB and the ER seem to have opposite effects (Table 1). For example, NF-κB activity has been shown to be required for the progression of several inflammatory and autoimmune diseases, such as a mouse model of multiple sclerosis [58], some mouse models of arthritis [59], inflammatory bowel disease [42] and atherosclerosis [60]. By contrast, enhanced ER activity lessens the severity of the same diseases 43, 61, 62, 63, 64, 65. An

Concluding remarks

The NF-κB and ER transcription factors have been studied extensively because of their important roles in physiology and pathology. The cross-talk between these transcription factors seems to be particularly relevant to bone physiology, inflammation, cancer and autoimmune diseases; however, the molecular mechanisms of inhibition of NF-κB by ER seem to be complex and are probably specific to cell type and context. Of note, another nuclear hormone receptor, the glucocorticoid receptor, is also a

Acknowledgements

We thank Gloria Callard, Ulla Hansen and members of our laboratory for comments on the manuscript. D.K. was supported in part by a National Institutes of Health (NIH) predoctoral training grant (T32-HD07387), and work in the authors' laboratory on NF-κB is supported by an NIH grant (CA47763) to T.D.G.

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