Interleukin-1α stimulates keratinocyte migration through an epidermal growth factor/transforming growth factor-α-independent pathway

Abstract

Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) stimulate keratinocyte migration on collagen by up-regulating the α2 subunit of the collagen integrin, α2β1. Interleukin-1 (IL-1) is an autocrine factor, produced by keratinocytes themselves, that is modulated by ultraviolet light and increases the proliferative potential of keratinocytes in culture. The autocrine nature of keratinocyte-derived IL-1α is emphasized by the fact that it induces the keratinocyte to synthesize IL-1α and TGF-α, a cytokine known to induce keratinocyte motility. Further, topical application of IL-1α has been shown to promote wound healing in animals. In this study, we used a well-defined keratinocyte migration assay to assess the effect of IL-1α on keratinocyte motility and to examine whether the IL-1α/ TGFα pathway is involved. The addition of recombinant human IL-1α to keratinocytes produced a statistically significant and concentration-dependent increase in migration on matrices of collagen types I and IV, but not on laminin. Maximal levels of keratinocyte migration obtained on these matrices with IL-1α were comparable to those obtained with stimulation by EGF and TGF-α. The effects of TGF-α and IL-1α on keratinocyte migration are additive; however, the maximal level of migration achieved by using IL-1α and TGF-α in combination never exceeds the maximal level of migration found by using either cytokine alone. The time course of keratinocyte migration induced by IL-1α is delayed (onset of migration 9-12 h after addition) as compared with that induced by TGF-α (onset of migration 6-9 h after addition) even if the cells are preincubated in IL-1α. Flow cytometry analysis demonstrated no change in surface expression of integrin subunits, specifically that of integrin subunit α2, previously shown to be up-regulated by EGF/TGF-α. These results suggest that IL-1α stimulates keratinocyte migration on collagen via a mechanism distinct from that of EGF/TGF-α.