TNF誘導的關節破壞由IL-1介導

TNF誘導的關節破壞由IL-1介導
Zwerina J, et al. PNAS.2007;104:11742-7.

TNF拮抗劑有效抑制人類類風溼關節炎(RA)的炎症和結構破壞。然而截至目前還不清楚TNF對其它參與子的上調做用是直接的仍是間接的。IL-1也許正是這些候選者之一，由於它在關節炎動物模型中也起重要做用，抑制IL-1也成功治療人類RA。

爲了去除TNF介導炎性關節病中IL-1的做用，咱們將IL-1alpha和IL-1beta均缺陷小鼠(IL-1-/-)與人TNF轉基因小鼠(hTNFtg)雜交。

基 於對IL-1缺陷單核細胞的一種固有分化障礙的檢測，與hTNFtg小鼠相比，IL-1-/-hTNFtg小鼠中IL-1缺陷幾乎不影響滑膜炎症的發生， 骨侵蝕和破骨細胞造成卻顯著減小。然而最具戲劇性的是，IL-1-/-hTNFtg小鼠中未見軟骨損傷。嵌合體研究揭示這種軟骨保護是因爲失去了IL-1 對造血細胞而非間充幹細胞的影響，致使ADAMTS-5和MMP-3表達下降。

這些數據代表TNF介導的軟骨破壞徹底是、而TNF介導的骨破壞部分是IL-1依賴性的，提示IL-1在炎性軟骨和骨破壞中是一個關鍵的參與者。

原文連接或參見如下信息。

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]