Role of Monocyte Chemoattractant Protein-1 (MCP-1) and regulation by NF-kB in Kawasaki disease

川崎病(KD)是一种病因不明的急性发热性脉管炎综合征，多见于日本儿童。在这个项目中，我们报道了单核细胞趋化蛋白-1在致死性KD中被巨噬细胞渗透的冠状动脉中的表达增强，提示单核细胞趋化蛋白-1在KD的发病机制中起作用。最近，相对于单核细胞趋化蛋白-1基因主要转录起始点的-2518(G或A)位的多态性被证明在体外影响单核细胞趋化蛋白-1的产生水平，以响应白细胞介素1β(Rovin Et Al)。我们用18名日本健康志愿者在体外复制了MCP-1的生产效果。携带-2518G等位基因(MCP-1的高产量)的日本人的PBMC比A等位基因(低产量的MCP-1)的受精卵产生更多的MCP-1(经非配对的韦尔奇t检验P&lt；0.01)，这与早期的一项研究一致。A等位基因在高加索和非裔美国人中占主导地位，表明可能存在种族变异。日本人群中的G/A基因多态性尚未被研究。在研究之前，所有受试者都获得了对本研究的知情同意。观察到的基因型和等位基因频率表明，G等位基因(MC-1的高产)在日本人群中占很大优势。A等位基因频率为35%，G等位基因频率为65%。此外，携带G等位基因的KD患者血清MCP-1水平高于携带A等位基因纯合子的KD患者，但经Mann-Whitney U检验，差异无统计学意义(p=0.24)。综上所述，日本人MCP-1基因远端调控区G等位基因的高频率可能提示在MCP-1产生的调节中存在潜在的重要种族变异，这可能是KD的发病机制之一。

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology preferentially affecting Japanese children. In this project, we reported an enhanced expression of MCP-1 in the coronary vessels infiltrated by macrophages in fatal KD, suggesting a role of MCP-1 in the pathogenesis of KD.Recently, the polymorphism at position -2518 (G or A), relative to the major transcriptional start site of the MCP-1 gene, was shown to influence the level of MCP-1 production in response to interleukin 1β in vitro (Rovin et al). We reproduced this in vitro effect of MCP-1 production using 18 Japanese healthy volunteers. PBMC from Japanese individuals who carry the -2518 G allele(high production of MCP-1) produced more MCP-1 than hoinozygotes for the A allele (low production of MCP-1) (p<0.01 by unpaired Welch's t test), consistent with an earlier study.The A allele was found to be predominant among Caucasian and African American populations, suggesting a possible ethnic variation. The G/A polymorphism in Japanese population has not been investigated. Informed consent for this study was obtained from all subjects before the study. The observed genotype and allele frequencies showed that G allele (high production of MC-1 was largely predominant among the Japanese population. The frequency of the A allele was 35 % and that of the G allele was 65 %. In addition, the serum levels of MCP-1 in KD patients with G allele were higher than those in homozygotes for the A allele, although the statistical significance was not obtained when tested by Mann-Whitney U test (p = 0.24). In conclusion, the high prevalence of G allele in the distal regulatory region of the MCP-1 gene in Japanese may suggest a potentially important ethnic variation in the regulation of MCP-1 production, which may contribute to the pathogenesis of KD.