The Pro-Inflammatory Cytokines IL-1β and TNFα Are Neurotrophic for Enteric Neurons
The Pro-Inflammatory Cytokines IL-1β and TNFα Are Neurotrophic for Enteric Neurons
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DOI：
10.1523/jneurosci.3564-12.2013
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发表时间：
2013-02-20
影响因子：
5.3
通讯作者：
Blennerhassett, Michael G.
中科院分区：
文献类型：
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作者：
Gougeon, P. -Y.;Lourenssen, Sandra;Blennerhassett, Michael G.
肠道炎症引起最初的轴突变性和神经元死亡，但随后幸存神经元的轴突生长恢复了目标平滑肌细胞的神经支配密度。在其他地方，促炎细胞因子 TNF α 和 IL-1 β 会引起神经毒性，因此我们需要测试它们在促进肠神经元死亡中的作用。在大鼠共培养模型中，TNF α 或 IL-1 β 不影响神经元数量，但在 48 小时时确实促进了显着的神经突生长，达到对照的两倍，而其他细胞因子（例如 IL-4、TGF β）则没有影响。 TNF α 或 IL-1 β 激活 NF kappa B 信号通路，抑制 NF kappa B 信号通路可阻断神经突生长的刺激。然而，NF kappa B 在平滑肌细胞中而非邻近神经元中的核易位表明平滑肌细胞具有主导作用。 TNF α或IL-1 β急剧增加GDNF的mRNA和蛋白质，而TNF α或IL-1 β的神经营养作用被RET受体阻断剂vandetanib阻断。来自细胞因子处理的平滑肌细胞的条件培养基模拟了神经营养作用，推断 TNF α 和 IL-1 β 通过 NF kappa B 依赖性诱导肠平滑肌细胞中胶质细胞系源性神经营养因子 (GDNF) 的表达来促进神经突生长。在体内，TNBS-结肠炎引起平滑肌细胞中 NF kappa B 的早期核转位。来自发炎结肠完整平滑肌的条件培养基导致共培养物中神经突数量增加 2.5 倍，而蛋白质印迹显示 GDNF 蛋白大幅增加。促炎细胞因子通过上调 GDNF 促进神经突生长，这是一种可能促进平滑肌细胞重新神经支配并在初始损伤后恢复稳态的新过程。
Intestinal inflammation causes initial axonal degeneration and neuronal death but subsequent axon outgrowth from surviving neurons restores innervation density to the target smooth muscle cells. Elsewhere, the pro-inflammatory cytokines TNF alpha and IL-1 beta cause neurotoxicity, leading us to test their role in promoting enteric neuron death. In a rat coculture model, TNF alpha or IL-1 beta did not affect neuron number but did promote significant neurite outgrowth to twofold that of control by 48 h, while other cytokines (e. g., IL-4, TGF beta) were without effect. TNF alpha or IL-1 beta activated the NF kappa B signaling pathway, and inhibition of NF kappa B signaling blocked the stimulation of neurite growth. However, nuclear translocation of NF kappa B in smooth muscle cells but not in adjacent neurons suggested a dominant role for smooth muscle cells. TNF alpha or IL-1 beta sharply increased both mRNA and protein for GDNF, while the neurotrophic effects of TNF alpha or IL-1 beta were blocked by the RET-receptor blocker vandetanib. Conditioned medium from cytokine-treated smooth muscle cells mimicked the neurotrophic effect, inferring that TNF alpha and IL-1 beta promote neurite growth through NF kappa B-dependent induction of glial cell line-derived neurotrophic factor (GDNF) expression in intestinal smooth muscle cells. In vivo, TNBS-colitis caused early nuclear translocation of NF kappa B in smooth muscle cells. Conditioned medium from the intact smooth muscle of the inflamed colon caused a 2.5-fold increase in neurite number in cocultures, while Western blotting showed a substantial increase in GDNF protein. Pro-inflammatory cytokines promote neurite growth through upregulation of GDNF, a novel process that may facilitate re-innervation of smooth muscle cells and a return to homeostasis following initial damage.