炎症性サイトカイン，血管新生促進因子，各種酵素の椎間板ヘルニア自然退縮機序における相互作用

Sequential Dynamics of Inflammatory Cytokines, Angiogenesis-inducing Factor, and Matrix-degrading Enzymes during Spontaneous Resorption of Herniated Disc

　抄録：椎間板ヘルニアの自然退縮機序を解明するため，その機序に必須とされている炎症性サイトカイン，血管新生促進因子，および各種タンパク分解酵素について，活性型マクロファージと椎間板組織による共培養モデルを用い，経時的発現パターンと各因子の相互作用について検討した．椎間板組織と活性型マクロファージの接触により，炎症性サイトカインであるTNF-αの強発現がまず認められ，次いで血管新生促進因子であるVEGFやマトリックス分解酵素であるu-PA，plasmin，MMPsの発現が認められた．また，u-PAの発現がTNF-αやVEGFによって促進されることも明らかとなった．これらより椎間板ヘルニア自然退縮機序のカスケードを想定した．TNF-αが炎症のイニシエーターとして働き，血管新生と各種酵素の発現を行うと考えられ，酵素間では，セリンプロテアーゼがMMPsの活性化に作用していることが示唆された．

　MRI analysis of herniated disc (HD) has revealed a spontaneous resorption mechanism related to neovascularization. Since interaction between activated macrophages with disc tissue appears to lead to the generation of inflammatory cytokines, and inflammatory cytokines, such as TNF-α, are required for induction of angiogenesis-inducing factors, such as VEGF, and matrix-degrading enzymes, such as MMP-3, MMP-7, and plasmin, we hypothesized that these molecules play a crucial role during spontaneous HD resorption. In this study we investigated the sequential expression of these molecules in a co-culture system in which activated macrophages and disc tissues interact as a model of the acute inflammatory response that occurs in HD. The results indicated that upregulation of both TNF-α mRNA and protein expression is the first to occur in the inflammation induced by HD. VEGF and u-PA upregulation follow the increase in TNF-α expression level, and plasmin and MMP-3 are upregulated later. We also found that both TNF-α and VEGF induce upregulation of u-PA expression, and our previous work demonstrated that TNF-α is capable of upregulating expression of VEGF, MMP-3, and MMP-7 in the co-culture system. We therefore postulated that TNF-α acts as the initiator of inflammation following contact between macrophages and disc chondrocytes. TNF-α could also act to accelerate the cascade of both angiogenesis and matrix degradation, thereby facilitating HD resorption. Further understanding of the resorption process may lead to novel therapies for HD in the future.