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Development of anti-skin ulcer drug based on the new concept -Application of the stimulatory effect of TNF-alpha on the production of NGF in fibroblasts

基于新概念的抗皮肤溃疡药物的开发-TNF-α刺激成纤维细胞产生NGF的作用的应用

基本信息

批准号：
07557378
负责人：
KOHNO Michiaki
金额：
$ 2.3万
依托单位：
Gifu Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

(1) A possible interaction between TNF-alpha and other cytokines in stimulating the production of NGF in Swiss 3T3 cells was investigated. TNF-alpha's stimulatory activity on fibroblasts NGF production was synergized by IL-1alpha/beta, IFN-gamma and BMP-2, but was antagonized by TGF-beta. These findings reinforce the idea that TNF-alpha, in concert with IL-1alpha/beta, IFN-gamma and BMP-2, plays an essential role in regulating the regeneration of peripheral nerve following injury through an indirect mechanism by which it stimulates NGF production in fibroblasts.(2) The role of the two types of TNF receptors, TNF-R1 and TNF-R2, in mediating the capacity of TNF to stimulate NGF productoin in fibroblasts was investigated. An agonistic anti-TNF-R1 antibody, but not an agonistic anti-TNF-R2 antibody, increased the NGF mRNA level and stimulated the NGF production in these cells, indicating that anti-TNF-R1 mediated the TNF's activity to stimulate the NGF gene expression. The post receptor signaling pathway leading to NGF gene expression, however, was unique and did not involve the activatoin of ERK MAP kinases, p38 MAP kinase, C kinase nor A kinase.(3) The effect of topical TNF-alpha on cutaneous wound repair with special reference to regeneration of peripheral nerve was investigated in C57BL-KsJ (ab/db JcL) mice that spontaneously develop type II Diabetes Melitus by applying it to full thickness skin wound in dorsal skin. Regression rate of wound was significantly higher in mice treated with 100 ng/cm^2 TNF-alpha than control. However, wound worsened in mice that received 1 and 10 mug/cm^2 TNF-alpha. Furthermore, regeneration of peripheral nerve was more apparent in the TNF-alpha-treated (100 ng/cm^2) group as compared with control. These results suggests that TNF-alpha at appropriate concentrations is expected to accelerate cutaneous wound healing, especially in terms of nerve regeneration.

(1)研究了TNF-α和其他细胞因子在刺激Swiss 3 T3细胞中NGF产生中的可能相互作用。TNF-α对成纤维细胞产生NGF的刺激活性被IL-1 α/β、IFN-γ和BMP-2协同，但被TGF-β拮抗。这些发现强化了这样的观点，即TNF-α与IL-1 α/β、IFN-γ和BMP-2一起，通过其刺激成纤维细胞中NGF产生的间接机制，在调节损伤后周围神经的再生中起重要作用。(2)研究了两种类型的TNF受体TNF-R1和TNF-R2在介导TNF刺激成纤维细胞产生NGF的能力中的作用。激动性抗TNF-R1抗体，而不是激动性抗TNF-R2抗体，在这些细胞中增加NGFmRNA水平并刺激NGF产生，表明抗TNF-R1介导TNF的活性以刺激NGF基因表达。然而，导致NGF基因表达的受体后信号通路是独特的，不涉及ERK MAP激酶、p38 MAP激酶、C激酶或A激酶的激活。(3)在自发发展II型糖尿病的C57 BL-KsJ（ab/db JcL）小鼠中，通过将局部TNF-α应用于背部皮肤中的全层皮肤伤口，研究了局部TNF-α对皮肤伤口修复（特别是外周神经再生）的作用。用100 ng/cm^2 TNF-α处理的小鼠的伤口消退率显著高于对照组。然而，在接受1和10 μ g/cm^2 TNF-α的小鼠中，伤口恶化。此外，与对照组相比，TNF-α治疗组（100 ng/cm ^2）的周围神经再生更明显。这些结果表明，TNF-α在适当的浓度，预计加速皮肤伤口愈合，特别是在神经再生方面。