TNF诱导的关节破坏由IL-1介导

TNF诱导的关节破坏由IL-1介导
Zwerina J, et al. PNAS.2007;104:11742-7.

TNF拮抗剂有效抑制人类类风湿关节炎(RA)的炎症和结构破坏。然而截至目前还不清楚TNF对其它参与子的上调作用是直接的还是间接的。IL-1也许正是这些候选者之一，因为它在关节炎动物模型中也起重要作用，抑制IL-1也成功治疗人类RA。

为了去除TNF介导炎性关节病中IL-1的作用，我们将IL-1alpha和IL-1beta均缺陷小鼠(IL-1-/-)与人TNF转基因小鼠(hTNFtg)杂交。

基
于对IL-1缺陷单核细胞的一种固有分化障碍的检测，与hTNFtg小鼠相比，IL-1-/-hTNFtg小鼠中IL-1缺陷几乎不影响滑膜炎症的发生，
骨侵蚀和破骨细胞形成却显著减少。然而最具戏剧性的是，IL-1-/-hTNFtg小鼠中未见软骨损伤。嵌合体研究揭示这种软骨保护是由于失去了IL-1
对造血细胞而非间充干细胞的影响，导致ADAMTS-5和MMP-3表达降低。

这些数据表明TNF介导的软骨破坏完全是、而TNF介导的骨破坏部分是IL-1依赖性的，提示IL-1在炎性软骨和骨破坏中是一个关键的参与者。

原文链接或参见以下信息。

Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11742-7. Epub 2007 Jul 3.
TNF-induced structural joint damage is mediated by IL-1.

Zwerina
J, Redlich K, Polzer K, Joosten L, Krönke G, Distler J, Hess A, Pundt
N, Pap T, Hoffmann O, Gasser J, Scheinecker C, Smolen JS, van den Berg
W, Schett G.
Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.

Blocking
TNF effectively inhibits inflammation and structural damage in human
rheumatoid arthritis (RA). However, so far it is unclear whether the
effect of TNF is a direct one or indirect on up-regulation of other
mediators. IL-1 may be one of these candidates because it has a central
role in animal models of arthritis, and inhibition of IL-1 is used as a
therapy of human RA. We removed the effects of IL-1 from a TNF-mediated
inflammatory joint disease by crossing IL-1alpha and beta-deficient mice
(IL-1-/-) with arthritic human TNF-transgenic (hTNFtg) mice.
Development of synovial inflammation was almost unaffected on IL-1
deficiency, but bone erosion and osteoclast formation were significantly
reduced in IL-1-/-hTNFtg mice, compared with hTNFtg mice based on an
intrinsic differentiation defect of IL-1-deficient monocytes. Most
dramatically, however, cartilage damage was absent in IL-1-/-hTNFtg
mice. Chimera studies revealed that protection of cartilage is based on
the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading
to decreased expression of ADAMTS-5 and MMP-3. These data show that
TNF-mediated cartilage damage is completely and TNF-mediated bone damage
is partially dependent on IL-1, suggesting that IL-1 is a crucial
mediator for inflammatory cartilage and bone degradation.

PMID: 17609389 [PubMed - indexed for MEDLINE]