Ferwerda Gerben, Kramer Matthijs, de Jong Dirk, Piccini Alessandra, Joosten Leo A, Devesaginer Isabel, Girardin Stephen E, Adema Gosse J, van der Meer Jos W M, Kullberg Bart-Jan, Rubartelli Anna, Netea Mihai G
Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Eur J Immunol. 2008 Jan;38(1):184-91. doi: 10.1002/eji.200737103.
Synthesis and release of pro-inflammatory cytokines, such as IL-1beta, play a crucial role in the intestinal inflammation that characterizes Crohn's disease. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are associated with an increased risk of Crohn's disease. Although it is known that NOD2 mediates cytokine responses to muramyl dipeptide (MDP), it is yet unclear whether NOD2 stimulation mediates only transcription of pro-IL-1beta mRNA, or whether NOD2 is also involved in the activation of caspase-1 and release of active IL-1beta. By investigating the response of MNC from Crohn's disease patients homozygous for the 3020insC NOD2 mutation, we were able to show that NOD2 signaling after stimulation with MDP has a dual effect by activating proIL-1beta mRNA transcription and inducing release of bioactive IL-1beta. Because NOD2 engagement amplifies TLR stimulation, we investigated whether activation of caspase-1 by MDP is involved in the NOD2/TLR synergism. The synergy in IL-1beta production between NOD2 and TLR is mediated at post-translational level in a caspase-1-dependent manner, which indirectly suggests that NOD2 also induces caspase-1 activation. In contrast, the synergy in TNF-alpha production after stimulation with MDP and LPS is induced at transcriptional level. This demonstrates that both caspase-1-dependent and -independent mechanisms are involved in the synergy between NOD2 and TLR.
促炎细胞因子（如白细胞介素-1β）的合成与释放，在以克罗恩病为特征的肠道炎症中起着关键作用。核苷酸寡聚化结构域2（NOD2）基因突变与克罗恩病风险增加相关。尽管已知NOD2介导细胞因子对胞壁酰二肽（MDP）的反应，但尚不清楚NOD2刺激是否仅介导前白细胞介素-1β mRNA的转录，或者NOD2是否也参与半胱天冬酶-1的激活及活性白细胞介素-1β的释放。通过研究3020insC NOD2突变纯合的克罗恩病患者的单核细胞（MNC）反应，我们能够证明用MDP刺激后的NOD2信号传导具有双重作用，即激活前白细胞介素-1β mRNA转录并诱导生物活性白细胞介素-1β的释放。由于NOD2的激活会放大Toll样受体（TLR）刺激，我们研究了MDP对半胱天冬酶-1的激活是否参与NOD2/TLR协同作用。NOD2和TLR之间白细胞介素-1β产生的协同作用在翻译后水平以半胱天冬酶-1依赖的方式介导，这间接表明NOD2也诱导半胱天冬酶-1激活。相比之下，用MDP和脂多糖（LPS）刺激后肿瘤坏死因子-α产生的协同作用在转录水平诱导。这表明半胱天冬酶-1依赖和非依赖机制均参与NOD2和TLR之间的协同作用。
