Immunoregulatory Defects In Inflammatory Bowel Disease

有很大比例的克罗恩病患者？这种疾病是炎症性肠病的一种，其CARD15 （NOD2）发生突变，这是一种细胞内蛋白，可识别常见细菌成分肽聚糖（PGN）的分解产物——muramyl二肽（MDP）。MDP通过CARD15信号及其亲本分子，PGN通过TLR2 （toll样受体2）信号激活关键的细胞内炎症开关NF-kappaB。因此，突变可能通过这些单独的信号通路干扰NF-kappaB的协调激活。在探索这种可能性的研究中，研究表明，缺乏CARD15的小鼠在受到PGN刺激时，单核细胞产生的IL-12、IL-18和ifn - γ显著增加，而不含MDP的TLR2刺激物通过TLR2刺激的正常单核细胞产生这些细胞因子受到MDP的抑制。由此可见，MDP正常下调PGN对炎症因子的诱导作用。在随后对这种下调的分子基础的研究中，研究表明CARD15信号传导导致PGN对NF-kappaB活化的抑制，特别是对c-Rel的活化，c-Rel是一种与IL-12的产生密切相关的NF-kappaB成分。最后，在探索这些机制是否确实解释了CARD15突变对克罗恩病的影响的研究中？将携带患者突变的CARD15基因引入CARD15缺陷细胞并不能纠正这些细胞异常的IL-12产生，而引入正常的CARD15基因却能纠正。综上所述，这些发现揭示了一种新的机制，通过这种机制对细菌产物的先天反应进行调节，并表明这种机制的异常可导致过量的IL-12产生和克罗恩病炎症。年代的疾病。

A significant percentage of patients with Crohn?s disease, a form of inflammatory bowel disease, have a mutation in CARD15 (NOD2) an intra-cellular protein that recognizes a breakdown product, muramyl dipeptide (MDP), of a common bacterial component, peptidoglycan (PGN). MDP via CARD15 signaling and its parent molecule, PGN via TLR2 (Toll-like Receptor 2) signaling activate the key intra-cellular inflammation switch, NF-kappaB. Thus, it was possible that the mutation disturbs the coordinate activation of NF-kappaB by these separate signaling pathways. In studies to explore this possibility, it was shown that mice lacking CARD15, manifest greatly increased IL-12, IL-18 and IFN-gamma production by monocytes when stimulated by PGN and that production of these cytokines by normal monocytes stimulated via TLR2 by TLR2 stimulants that do not contain MDP was inhibited by MDP. From this it was evident that MDP normally down-regulates PGN induction of inflammatory cytokines. In subsequent studies of the molecular basis of this down-regulation it was shown that CARD15 signaling leads to inhibition of PGN induction of NF-kappaB activation, particularly the activation of c-Rel, an NF-kappaB component closely associated with the production of IL-12. Finally, in studies to explore whether these mechanisms do indeed explain the effect of CARD15 mutations in Crohn?s disease: introduction of a CARD15 gene bearing the patient mutation into CARD15-deficient cells did not correct the abnormal IL-12 production of these cells whereas introduction of a normal CARD15 gene did lead to correction. Taken together, these findings reveal a new mechanism by which innate responses to bacterial products are regulated and show that an abnormality of this mechanism can lead to excess IL-12 production and the inflammation of Crohn?s disease.