Abstract
Estrogen has pleiotropic actions, among which are its anti-apoptotic, anti-inflammatory, and vasodilatory effects. Recently, an interaction between 17beta-estradiol (E2) and the transcription factor nuclear factor kappaB (NFkappaB) has been identified. NFkappaB has a central role in the control of genes involved in inflammation, proliferation, and apoptosis. Prolonged activation of NFkappaB is associated with numerous inflammatory pathological conditions. An important facet of E2 is its ability to modulate activity of NFkappaB via both genomic and nongenomic actions. E2 can activate NFkappaB rapidly via nongenomic pathways, increase cellular resistance to injury, and induce expression of the protective class of proteins, heat shock proteins (HSPs). HSPs can bind to many of the pro-apoptotic and pro-inflammatory targets of NFkappaB and, thus, indirectly inhibit many of its deleterious effects. In addition, HSPs can block NFkappaB activation and binding directly. Similarly, genomic E2 signaling can inhibit NFkappaB, but does so through alternative mechanisms. This review focuses on the molecular mechanisms of cross-talk between E2, NFkappaB, and HSPs, and the biological relevance of this cross-talk.
Highlights
Estrogen is known to induce a number of beneficial physiological effects, especially in the neurologic and cardiovascular systems
Overexpression of heat shock factor (HSF)-1 in mammalian cells leads to spontaneous binding to the heat shock element (HSE) in the absence of heat shock, but, under normal conditions, HSF-1 is in a multi-protein complex, and heat and other stresses are necessary for its activation [75]
A later response to E2 results in the inhibition of nuclear factor κB (NFκB). This may be mediated by activation of HSF-1 and heat shock proteins (HSPs) expression, but this has not been proven
Summary
Estrogen is known to induce a number of beneficial physiological effects, especially in the neurologic and cardiovascular systems. Acute inflammation alerts effector cells of potentially harmful stimuli, longterm cytokine expression can induce cell death through the extrinsic apoptotic pathway and lead to activation of proapoptotic signaling cascades, such as Jun N-terminal kinase (JNK), that normally is suppressed upon NFκB activation. Many pathological conditions, such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and cancer are linked to constitutive NFκB activation. E2 inhibits the effects of inflammatory transcription factors, including AP-1 and NFκB, when activated, induces the expression of cytokines, inflammatory enzymes, adhesion molecules, and inflammatory receptors [15]
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