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Keloids are proliferative dermal growths representing a pathologic wound healing response. We have previously demonstrated that coculture of fibroblasts derived from either keloid or normal skin have an elevated proliferation rate when cocultured with keloid-derived keratinocytes vs. normal keratinocytes. In these studies, we examined the contribution of transforming growth factor-β (TGF-β) to this phenomenon using a two-chamber coculture system. Fibroblast proliferation in coculture was slower with the addition of a pan-TGF-β neutralizing antibody. Keloid keratinocytes in coculture expressed more TGF-β1, -β3, and TGF-β receptor 1 than normal keratinocytes. Keloid fibroblasts cocultured with keloid keratinocytes expressed more mRNA for TGF-β1, -β2, TGF-β receptor 1, and Smad2. Keloid fibroblasts also produced more type I collagen, connective tissue growth factor, and insulin-like growth factor-II/mannose-6-phosphate receptor when cocultured with keloid keratinocytes vs. normal keratinocytes. Levels of total and activated TGF-β activity increased when fibroblasts were cocultured with keratinocytes, correlating with the changes in transcriptional activity of TGF-β. In conclusion, we find a complex paracrine interaction regulates TGF-β mRNA expression and activation between keratinocytes and fibroblasts. These data suggest that keloid pathogenesis may result from both an increased TGF-β production and activation by the keloid keratinocyte, and elevated TGF-β expression, utilization, and signaling in keloid fibroblasts.