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Identification of an IL-6 induced keratinocyte motogen

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In the United States, over 6 million individuals develop chronic skin ulcers annually. The augmentation of cutaneous wound healing has long been an elusive goal for health care professionals. Our previous studies indicate that interleukin-6 deficient transgenic mice (IL-6KO) display significantly delayed cutaneous wound healing compared to wild type control animals. While the role of IL-6 is well documented in disease conditions such as psoriasis, little is known about the role this cytokine might play in regenerative responses such as wound healing. To further describe the role of IL-6 in skin wound healing, an in vitro model was developed utilizing cultured epidermal keratinocyte and dermal fibroblast cells from neonatal IL-6KO mice. This system allows for the direct assessment of the effects of IL-6 on skin cells without the confounding presence of endogenous IL-6. Using this culture system we have found that IL-6 appears to significantly induce cell motility, in cultured keratinocytes. However, this effect appears to be indirect and requires co-culture with dermal fibroblasts. Preliminary gene array experiments do not indicate the induction of a secreted protein known to induce keratinocyte migration. In this application we propose to: 1) characterize and 2) identify the IL-6-induced dermal fibroblast produced migratory factor. To do this, further gene array experiments will be conducted with IL-6KO dermal fibroblasts exposed to IL-6, and epidermal keratinocytes exposed to IL-6/fibroblast conditioned media. IL- 6/fibroblast conditioned media will also be concentrated, and ion exchange chromatography will be performed. Isolated IL-6KO keratinocytes will be exposed to fractions collected from the chromatographic separations, and migratory potential will be assessed. Fractions that induce a migratory response will be subject to proteomic analysis utilizing 2D gel seperation and tryptic fingerprinting will be determined with a MALDI-TOF mass spectrometer. Once identified, the motogenic potential of migratory factor(s) will be assessed on isolated keratinocytes from IL-6KO and wild type mice. The results of these experiments will hopefully lead to the eventual development of a useful treatment for chronic wounds.
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