NF-κB-Inducing Kinase Is Dispensable for Activation of NF-κB in Inflammatory Settings but Essential for Lymphotoxin β Receptor Activation of NF-κB in Primary Human Fibroblasts1
NF-κB-Inducing Kinase Is Dispensable for Activation of NF-κB in Inflammatory Settings but Essential for Lymphotoxin β Receptor Activation of NF-κB in Primary Human Fibroblasts1
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DOI：
10.4049/jimmunol.167.10.5895
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发表时间：
2001-11
期刊：
影响因子：
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通讯作者：
Clive W. Smith;E. Andreakos;J. Crawley;F. Brennan;M. Feldmann;B. Foxwell
中科院分区：
文献类型：
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作者：
Clive W. Smith;E. Andreakos;J. Crawley;F. Brennan;M. Feldmann;B. Foxwell
转录因子NF-κB在促炎细胞因子如TNF-α和IL-1α的生物学中具有重要意义，因此与炎症过程密切相关。了解NF-κB B在炎症反应中的活化机制已成为炎症研究的主要目标。NF-κ B诱导激酶（NIK）是一种与肿瘤坏死因子受体（TNFR）相关的因子相互作用的酶，是IκBα-激酶复合物的潜在激活剂，这一发现似乎确定了NF-κB激活途径的一个重要元件，这一观点得到了后续研究的支持。然而，最近的实验在淋巴发育不全（aly/aly）小鼠，其中有错义点突变（G885 R）在NIK，挑战了这一观点。不同研究之间差异的原因尚不清楚，可能是由于多种因素，如细胞类型、细胞种属或原代细胞系与转化细胞系。一个尚未被研究的系统是原代人类细胞。利用编码激酶缺陷型NIK的腺病毒载体，我们研究了NIK在原代人细胞中LPS、IL-1、TNF-α和LPS（LT）βR信号传导以及类风湿组织中TNF-α表达中的作用。这些数据表明，在测试的主要系统中，NIK在LTβR信号传导中具有有限的作用，并且不需要测试的其他刺激。此外，在人类类风湿性关节炎中，NIK在TNF-α产生过程中没有明显作用。这些数据也突出了在推断原代细胞系和转染细胞系之间的信号传导途径的功能方面的潜在问题。
The transcription factor NF-κB is of major importance in the biology of pro-inflammatory cytokines, such as TNF-α and IL-1α, and thereby is intimately involved in the process of inflammation. Understanding the mechanisms by which NF-κB is activated in response to inflammatory stimuli has become a major goal of inflammation research. The discovery of NF-κB-inducing kinase (NIK) as a TNFR-associated factor-interacting enzyme and a potential activator of the IκBα-kinase complex appeared to have identified an important element of the NF-κB activition pathway, a view that was supported by several subsequent studies. However, recent experiments in the alymphoplasia (aly/aly) mouse, which has missense point mutation (G885R) in NIK, has challenged that view. The reasons for the discrepancy between the different studies is unclear and could be due to multiple factors, such as cell type, species of cell, or primary vs transformed cell lines. One system that has not been investigated is primary human cells. Using an adenoviral vector encoding kinase-deficient NIK, we have investigated the role of NIK in LPS, IL-1, TNF-α, and lymphotoxin (LT) βR signaling in primary human cells and TNF-α expression from rheumatoid tissue. These data show that, in the primary systems tested, NIK has a restricted role in LTβR signaling and is not required by the other stimuli tested. Also, there is no apparent role for NIK in the process of TNF-α production in human rheumatoid arthritis. These data also highlight the potential problems in extrapolating the function of signaling pathways between primary and transfected cell lines.