Interleukin-1β released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors
Interleukin-1β released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors
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DOI：
10.1074/jbc.m602156200
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发表时间：
2006-10-06
影响因子：
4.8
通讯作者：
Marinovich, Marina
中科院分区：
文献类型：
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作者：
Viviani, Barbara;Gardoni, Fabrizio;Marinovich, Marina
白细胞介素-1 β是一种促炎细胞因子，涉及NMDA受体激活的病理条件，包括艾滋病痴呆复合体（HAD）。在这种情况下产生的天然白细胞介素-1 β招募的分子机制尚无信息。通过对原代海马神经元和神经胶质细胞的三明治共培养，我们研究了由hiv -gp120激活的神经胶质细胞释放的天然白细胞介素-1 β是否(i)影响NMDAR功能，（ii）与神经元脊柱密度和存活的相关性，这是HAD的两个特定特征。神经元暴露于600 pM gp120 24小时后，NR2B tyr1 -1472磷酸化增加。这种作用仅在神经胶质细胞存在的情况下发生，并被白细胞介素-1受体拮抗剂（IL-1ra）消除。gp120诱导的NR2B磷酸化导致神经元细胞内Ca2+持续升高，NR2B与PSD95的结合显著增加。通过白细胞介素-1ra和Ca-pYEEIE （Src家族SH2抑制剂肽）选择性抑制含有NR2B的受体，10 μ M的非苯丙地尔可以阻止细胞内Ca2+的增加。最后两种抑制剂也能阻止NR2B与PSD95的结合。最后，gp120在治疗48 h后使PSD95总阳性棘密度降低35%，并诱导30%的神经元死亡。同样，这两种作用都被Ca-pYEEIE阻断了。总之，我们的数据表明gp120从胶质细胞释放白介素-1 β增加NMDAR的酪氨酸磷酸化。因此，酪氨酸磷酸化可能有助于受体的敏化，增加其功能和突触定位。这两种影响都与神经变性有关。
Interleukin-1 beta is a proinflammatory cytokine implicated under pathological conditions involving NMDA receptor activation, including the AIDS dementia complex ( HAD). No information is available on the molecular mechanisms recruited by native interleukin-1 beta produced under this type of condition. Using a sandwich co-culture of primary hippocampal neurons and glia, we investigated whether native interleukin-1 beta released by HIV-gp120-activated glia (i) affects NMDAR functions and (ii) the relevance on neuronal spine density and survival, two specific traits of HAD. Increased phosphorylation of NR2B Tyr-1472 was observed after 24 h of exposure of neurons to 600 pM gp120. This effect occurred only when neurons were treated in the presence of glial cells and was abolished by the interleukin-1 receptor antagonist (IL-1ra). Gp120-induced phosphorylation of NR2B resulted in a sustained elevation of intracellular Ca2+ in neurons and in a significant increase of NR2B binding to PSD95. Increased intracellular Ca2+ was prevented by 10 mu M ifenprodil, that selectively inhibits receptors containing the NR2B, by interleukin-1ra and by Ca-pYEEIE, a Src family SH2 inhibitor peptide. These last two inhibitors, prevented also NR2B binding to PSD95. Finally, gp120 reduced by 35% of the total PSD95 positive spine density after 48 h of treatment and induced by 30% of the neuronal death. Again, both of these effects were blocked by Ca-pYEEIE. Altogether, our data show that gp120 releasing interleukin-1 beta from glia increases tyrosine phosphorylation of NMDAR. Thus, tyrosine phosphorylation may contribute to the sensitization of the receptor increasing its function and synaptic localization. Both of these effects are relevant for neurodegeneration.