Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats

Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examined the effects of ER alpha- and ER beta-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17 beta-estradiol (ER alpha/ER beta agonist), HPTE (ER alpha agonist/ER beta antagonist) and DPN (ER beta agonist) led to attenuation of IL-1 beta, TNF alpha, and NIMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ER alpha agonist) attenuated IL-1 beta (but not MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17 beta-estradiol was unable to attenuate the LPS-induced increase in IL-1 beta in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1 beta was not attenuated by pre-treatment with 17 beta-estradiol, PPT or HPTE. Interestingly, the ER beta agonist, DPN significantly decreased IL-1 beta following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compounds which bind ER beta are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use. (C) 2008 Elsevier B.V. All rights reserved.