Estrogen or Estrogen Receptor Agonist Inhibits Lipopolysaccharide Induced Microglial Activation and Death

Abstract

Inflammation is an important pathogenic mechanism in many neurodegenerative disorders. Activated microglia play a pivotal role in releasing proinflammatory factors including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) for inducing inflammation. While microglia mediated inflammation is essential in maintaining CNS homeostasis, chronic inflammation results in activation of proteases for cell death. Here, we examined the effect of PPT (estrogen receptor α agonist), DPN (estrogen receptor β agonist), and estrogen on rat primary microglia following exposure to lipopolysaccharide (LPS). Exposure of microglia to LPS (200 ng/ml) for 24 h induced cell death. After LPS toxicity for 15 min, microglia were treated with 25 nM PPT, 25 nM DPN, or 100 nM estrogen that prevented cell death by attenuating the release of IL-1α, IL-1β, TNF-α, and COX-2. Treatment of cells with 100 nM fulvestrant (estrogen receptor antagonist) prior to addition of PPT, DPN, or estrogen significantly decreased their ability to prevent cell death, indicating involvement of estrogen receptor (ER) in providing PPT, DPN, or estrogen mediated cytoprotection. Reverse transcriptase polymerase chain reaction (RT–PCR) analyses showed alterations in mRNA expression of Bax, Bcl-2, calpain, and calpastatin during apoptosis. We also examined mRNA expression of ERβ and ERα following exposure of microglia to LPS and subsequent treatment with PPT, DPN, or estrogen. We found that estrogen or estrogen receptor agonists upregulated expression of ERs. Overall, results indicate that estrogen receptor agonist or estrogen uses a receptor mediated pathway to protect microglia from LPS toxicity.

Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males

“…They found that neonatal LPS exposure at postnatal day 14 caused elevated basal expression of hypothalamic COX-2 in the male, but not in the female rats. Similarly, Smith et al (2011) found that estrogen or estrogen receptor agonists inhibited LPS-induced microglial activation and death in the brain in rats. Specifically, estrogen prevented cell death by attenuating the release of interleukin-1-alpha, interleukin-1-beta, tumor necrosis factor-α, and COX-2.…”

Complex interplay between tumor microenvironment and cancer therapy

“…Previous studies suggest that hormone therapy could modulate TME which then induces treatment resistance. Specifically, it has been observed that cytokine profile in the TME was changed upon ERα suppression, for example, IL-1β level is significantly unregulated [107]. In presence of IL-1β, tamoxifen acts as an agonist rather than an antagonist, and promotes tumor progression [108].…”

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

“…The inhibitory effects of PPT and DPN on many neurological disorders have been confirmed by other studies. 7,18,32,45,53 The receptors ERa and ERb are essential for E2-mediated regulation of BBB permeability, antiinflammatory properties, the production of interleukins in the brain, and regulation of neutrophil recruitment into the brain. 7 Both ER agonists reduce the inflammatory response 45 and take part in the control of inflammation by estradiol, 18 neuromodulation, and neuroprotection processes after brain injury.…”

“…7,18,32,45,53 The receptors ERa and ERb are essential for E2-mediated regulation of BBB permeability, antiinflammatory properties, the production of interleukins in the brain, and regulation of neutrophil recruitment into the brain. 7 Both ER agonists reduce the inflammatory response 45 and take part in the control of inflammation by estradiol, 18 neuromodulation, and neuroprotection processes after brain injury. 27,34,53 There are several probable mechanisms by which ERa and ERb attenuate BBB permeability and brain edema after TBI that result from the inflammatory response: upregulation of defensin genes, IL-6, MMP-9, MHC (major histocompatibility complex) antigen genes, and some of phagocytic receptors; 40,54 protection of cortical cells against oxidative glutamate toxicity; 59 neuroprotection of estrogen against activated microglia; 4 inhibition of the cytoplasmic transport of NF-kB (a transcription factor for inflammatory genes); 54,56 induction of activity of the phosphoinositol-3 kinase and Akt;…”