Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.
Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.
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发表时间：
2005
期刊：
影响因子：
3.8
通讯作者：
Jong-In Park;C. Strock;D. Ball;B. Nelkin
中科院分区：
文献类型：
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作者：
Jong-In Park;C. Strock;D. Ball;B. Nelkin
白细胞介素-1 β（IL-1 β）是一种多效性细胞因子，可诱导多种细胞信号转导途径。在这里，我们发现IL-1 β可以诱导人甲状腺髓样癌（MTC）细胞系TT的细胞周期阻滞和分化。IL-1 β诱导细胞周期阻滞，伴随着形态学变化和神经内分泌标志物降钙素的表达。这些变化被MEK 1/2特异性抑制剂U 0126阻断，表明MEK 1/2对TT细胞中的IL-1 β信号传导至关重要。IL-1 β通过MEK/ERK途径诱导白血病抑制因子（LIF）的表达和STAT 3的活化。用抗LIF中和抗体或抗gp 130阻断抗体处理可以消除STAT 3的这种激活，表明LIF表达的诱导对于IL-1 β激活STAT 3是充分和必要的。除了激活LIF/JAK/STAT通路外，IL-1 β还诱导MEK/ERK介导的细胞内细胞自主信号传导通路，该通路独立地足以进行生长停滞和分化。因此，IL-1 β激活MEK/ERK通路，通过细胞外LIF/JAK/STAT通路和细胞内自主信号通路这两种独立的信号机制诱导MTC细胞的生长停滞和分化。
Interleukin-1beta (IL-1beta) is a pleiotropic cytokine that can induce several cellular signal transduction pathways. Here, we show that IL-1beta can induce cell cycle arrest and differentiation in the human medullary thyroid carcinoma (MTC) cell line, TT. IL-1beta induces cell cycle arrest accompanied by morphological changes and expression of the neuroendocrine marker calcitonin. These changes are blocked by the MEK1/2 specific inhibitor U0126, indicating that MEK1/2 is essential for IL-1beta signaling in TT cells. IL-1beta induces expression of leukemia inhibitory factor (LIF) and activation of STAT3 via the MEK/ERK pathway. This activation of STAT3 could be abrogated by treatment with anti-LIF neutralizing antibody or anti-gp130 blocking antibody, indicating that induction of LIF expression is sufficient and essential for STAT3 activation by IL-1beta. In addition to activation of the LIF/JAK/STAT pathway, IL-1beta also induced an MEK/ERK-mediated intracellular cell-autonomous signaling pathway that is independently sufficient for growth arrest and differentiation. Thus, IL-1beta activates the MEK/ERK pathway to induce growth arrest and differentiation in MTC cells via dual independent signaling mechanisms, the cell-extrinsic LIF/JAK/STAT pathway, and the cell-intrinsic autonomous signaling pathway.