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Objective: To determine whether the anti-inflammatory effects of leukemia inhibitory factor (LIF) are altered in aged male and female rats.Methods: Focal ischemia was induced in 3 month old male and 18 month old male/female Sprague-Dawley using the middle cerebral artery occlusion (MCAO) procedure. Animals were treated with PBS or LIF at 6, 24, and 48 h after MCAO (125 μg/kg). Infarct volume in aged animals was quantified with T2-weighted MRI. Functional motor skills were assessed immediately prior to euthanization at 72 h post-MCAO. Protein levels of CD11b and IL-12 p40 in brain and spleen tissue were measured using immunoblotting.Results: At 72 h, there was a trend towards decreased infarct volume in aged male (189 ± 45OD; n=4) and female LIF-treated rats (104 ± 71 OD; n=4) compared to PBS-treated aged male (188 ± 45; n=4) and female rats (179 ± 72; n=5). LIF-treated aged female rats showed significant decreases in circling (p=0.0209) and body swing bias (p=0.05) compared to the PBS-treated aged females. Normalized CD11b levels were significantly in LIF-treated young males (1.1 ± 0.3 OD; n=5) compared to PBS-treated young males (2.5 ± 0.5 OD; n=6; p<0.05). Although aged male (1.2 ± 0.4 OD) and females (1.2 ± 0.3 OD) had lower levels of CD11b in the brain 72 h post-MCAO compared to young males, LIF had no effect on brain CD11b levels in aged rats. LIF increased spleen size (1.6 ± 0.1 g) and splenic CD11b levels (0.11 ± 0.01 OD) compared to PBS-treated females (0.6 ± 0.1 g; 0.08 ± 0.01 OD; p<0.05), and there was a significant positive correlation between these two factors in the aged female rats (r = 0.6775; p<0.05). Furthermore, IL-12 p40 levels in splenic tissue were significantly higher in young male PBS-treated rats (0.38 ± 0.06 OD) compared to aged male (0.12 ± 0.01 OD; p<0.01) and female rats (0.16 ± 0.04 OD; p<0.01). LIF treatment reduced IL-12 p40 levels in the spleen in young rats (0.24 ± 0.04; p<0.05) but not in either of the aged rat groups.Conclusions: LIF is more effective at decreasing splenic IL-12 expression and immune cell infiltration in young rats compared to aged rats. However, LIF counteracts the post-stroke splenic response in aged females but not aged male rats.