Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury.
Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury.
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DOI：
10.1016/j.imlet.2008.08.007
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发表时间：
2008-11-16
影响因子：
4.4
通讯作者：
Putterman, Chaim
中科院分区：
文献类型：
--
作者：
Qing, Xiaoping;Pitashny, Milena;Thomas, David B.;Barrat, Franck J.;Hogarth, Mark P.;Putterman, Chaim
虽然抗dna抗体与狼疮性肾炎的发病机制有决定性的联系，但其机制尚未得到最终确定。最近，我们报道了抗dna抗体可能通过上调系膜细胞（MC）中的促炎基因而导致肾损伤，这一过程涉及Fc受体依赖和独立途径。在研究致病性抗dna抗体调节MC基因表达的机制时，我们发现致病性抗dna抗体1A3F与高迁移率基团结合蛋白1 （HMGB1）结合，HMGB1是TLR2/4和RAGE（晚期糖基化终产物受体）的内源性配体。有趣的是，HMGB1对MC的处理诱导了与1A3F刺激相似的基因模式。此外，HMGB1和1A3F在肾脏中表现出协同促炎作用，其中在狼疮患者中发现HMGB1表达增加，而在其他类型肾脏疾病患者中则没有。TLR2/Fc和RAGE/Fc抑制了1A3F对MC的促炎作用。最后，我们发现，与正常BALB/c衍生的MC相比，狼疮易感性MRL-lpr/lpr （MRL/lpr）对致病性抗dna抗体和LPS刺激（特别是趋化因子合成增强）的易感性增强，此外TLR4的表达显著增加。我们的研究结果表明，肾源性抗dna抗体诱导的MC基因上调是TLR2/4和RAGE依赖的。最后，HMGB1可能在系统性红斑狼疮（SLE）抗体诱导的肾损害中起到促炎介质的作用。
Although anti-DNA antibodies have been decisively linked to the pathogenesis of lupus nephritis, the mechanisms have not been conclusively determined. Recently, we reported that anti-DNA antibodies may contribute to kidney damage by upregulation of proinflammatory genes in mesangial cells (MC), a process involving both Fc receptor dependent and independent pathways. In investigating the mechanism by which pathogenic anti-DNA antibodies modulate gene expression in MC, we found that the pathogenic anti-DNA antibody 1A3F bound to high mobility group binding protein 1 (HMGB1), an endogenous ligand for TLR2/4 and RAGE (receptor for advanced glycation end-products). Interestingly, HMGB1 treatment of MC induced a similar pattern of genes as stimulation with 1A3F. Furthermore, HMGB1 and 1A3F exhibited a synergistic proinflammatory effect in the kidney, where increased expression of HMGB1 was found in lupus patients but not in patients with other types of renal disease. TLR2/Fc and RAGE/Fc inhibited the proinflammatory effects of 1A3F on MC. Finally, we found enhanced susceptibility of lupus prone MRL-lpr/lpr (MRL/lpr) as compared to normal BALB/c derived MC to pathogenic anti-DNA antibody and LPS stimulation (in particular enhanced chemokine synthesis), in addition to significantly increased expression of TLR4. Our results suggest that gene upregulation in MC induced by nephritogenic anti-DNA antibodies is TLR2/4 and RAGE dependent. Finally, HMGB1 may act as a proinflammatory mediator in antibody induced kidney damage in systemic lupus erythematosus (SLE).
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影响因子：
15.9
作者：
EMLEN, W;ANSARI, R;BURDICK, G
通讯作者：
BURDICK, G
影响因子：
4.4
作者：
Deocharan, B;Qing, XP;Putterman, C
通讯作者：
Putterman, C
影响因子：
2.6
作者：
Barkauskaite, V.;Ek, M.;Nyberg, F.
通讯作者：
Nyberg, F.
影响因子：
4.4
作者：
Fu, YY;Xie, C;Mohan, C
通讯作者：
Mohan, C
DOI：
10.1084/jem.20030132
发表时间：
2004-02-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liang Z;Xie C;Chen C;Kreska D;Hsu K;Li L;Zhou XJ;Mohan C
通讯作者：
Mohan C