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Proliferation and differentiation of keratinocytes are normally well balanced, but this balance can be perturbed in wound healing and is dysregulated in pathological conditions such as atopic dermatitis. Epithelial–mesenchymal interaction affects this event via the cross-talk of cytokines and growth factors. Periostin, a matricellular protein, has an important role during reepithelialization in wound healing and is critical for hyperproliferation of keratinocytes in atopic dermatitis. Here we investigated how periostin regulates proliferation and differentiation of keratinocytes in the epithelial–mesenchymal interactions using a three-dimensional organotypic air–liquid interface coculture system. The release of IL-1α from keratinocytes and subsequent IL-6 production from fibroblasts were critical for keratinocyte proliferation and differentiation. Periostin secreted from fibroblasts was required for IL-1α-induced IL-6 production and enhanced IL-6 production by activation of the NF-κB pathway synergistically with IL-1α. Thus, the combination of an autocrine loop of periostin and a paracrine loop composed of IL-1α and IL-6 regulates keratinocyte proliferation and differentiation in the epithelial–mesenchymal interactions, and periostin tunes the magnitude of keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop.