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 ERα-and ERβ-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17β-estradiol (ERα/ERβ agonist), HPTE (ERα agonist/ERβ antagonist) and DPN (ERβ agonist) led to attenuation of IL-1β, TNFα, and MMP-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 (ERα agonist) attenuated IL-1β (but not TNFα or MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17β-estradiol was unable to attenuate the LPS-induced increase in IL-1β 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-1β was not attenuated by pre-treatment with 17β-estradiol, PPT or HPTE. Interestingly, the ERβ agonist, DPN significantly decreased IL-1β 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 ERβ are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.