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

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(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.