Role of Interleukin-4 in Regulation of Age-related Inflammatory Changes in the Hippocampus

Abstract

It is well documented that long term potentiation (LTP) is impaired in the hippocampus of the aged animal. Among the changes that contribute to this impairment is an increase in hippocampal concentration of the pro-inflammatory cytokine interleukin-1␤ (IL-1␤), and increased IL-1␤-induced signaling. In this study we investigated the possibility that these changes were a consequence of decreased concentration of the anti-inflammatory cytokine, IL-4, and decreased IL-4-stimulated signaling. We report that functional IL-4 receptors are expressed on granule cells of the dentate gyrus and that receptor activation results in phosphorylation of JAK1 and STAT6. Hippocampal IL-4 concentration was decreased with age, and this was accompanied by a decrease in phosphorylation of JAK1 and STAT6. The evidence indicates that IL-4 modulates expression of IL-1␤ mRNA and protein and that it attenuates IL-1␤-induced impairment of LTP and phosphorylation of JNK and c-Jun. We argued that, if a decrease in hippocampal IL-4 concentration significantly contributed to the age-related impairment in LTP, then restoration of IL-4 should restore LTP. To test this, we treated rats with VP015 (phospholipid microparticles-incorporating phosphatidylserine), which increases IL-4 concentration in hippocampus. The data indicate that the VP015-induced increase in IL-4 concentration in hippocampus of aged rats and lipopolysaccharide (LPS)-treated rats was accompanied by a reversal of the age-related and LPSinduced impairment in LTP in perforant path granule cell synapses. We propose that interplay between proinflammatory and anti-inflammatory responses impact significantly on synaptic function in the hippocampus of the aged rat.Inflammatory changes contribute to the deficits that accompany several neurodegenerative conditions, and, in animal models, it has been repeatedly shown that inflammation is associated with deficits in synaptic function and consequently impairments in cognitive function. For example, peripheral administration of lipopolysaccharide (LPS 1 ), which increases pro-inflammatory cytokine interleukin-1␤ (IL-1␤) concentration in the brain, is accompanied by evidence of cell stress and neuronal cell death (1, 2) as well as impairment of hippocampaldependent learning and memory (3). Deficits in long term potentiation (LTP) have been reported in aged rats (4) and in other experimental conditions in which hippocampal IL-1␤ concentration is increased (5-9). Significantly, administration of anti-inflammatory agents restores synaptic function in LPStreated animals in which IL-1␤ concentration is enhanced (6, 10, 11).Inflammatory responses are regulated in part by anti-inflammatory cytokines, including IL-4 and IL-10, which are produced by T cells and cells of the innate immune system. T helper type 2 (Th2) cells secrete IL-4, IL-5, and IL-10 and are responsible for reciprocally regulating the T helper type 1 (Th1) subtype, which mediate cellular and inflammatory responses. IL-4 also plays a role in promoting the differentiation of naïve T ce...

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

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CD200 Ligand–Receptor Interaction Modulates Microglial ActivationIn VivoandIn Vitro: A Role for IL-4

“…The data have indicated that the age-related decrease in hippocampal IL-4 concentration contributed to the increase in IL-1␤ and the associated deficit in LTP, whereas intracerebroventricular injection of IL-4 attenuated these changes (Barry et al, 2005;Nolan et al, 2005). Recent evidence has revealed that IL-4 inhibits the A␤ induced in MHCII mRNA expression and the increase in pro-inflammatory cytokine production, whereas it blocks the A␤-induced inhibition of LTP (Lyons et al, 2007).…”

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