Interleukin-1 alpha stimulates keratinocyte migration through an epidermal growth factor/transforming growth factor-alpha-independent pathway.
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) stimulate keratinocyte migration on collagen by up-regulating the alpha 2 subunit of the collagen integrin, alpha 2 beta 1. 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-1 alpha is emphasized by the fact that it induces the keratinocyte to synthesize IL-1 alpha and TGF-alpha, a cytokine known to induce keratinocyte motility. Further, topical application of IL-1 alpha 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-1 alpha on keratinocyte motility and to examine whether the IL-1 alpha/TGF alpha pathway is involved. The addition of recombinant human IL-1 alpha 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-1 alpha were comparable to those obtained with stimulation by EGF and TGF-alpha. The effects of TGF-alpha and IL-1 alpha on keratinocyte migration are additive; however, the maximal level of migration achieved by using IL-1 alpha and TGF-alpha in combination never exceeds the maximal level of migration found by using either cytokine alone. The time course of keratinocyte migration induced by IL-1 alpha is delayed (onset of migration 9-12 h after addition) as compared with that induced by TGF-alpha (onset of migration 6-9 h after addition) even if the cells are preincubated in IL-1 alpha. Flow cytometry analysis demonstrated no change in surface expression of integrin subunits, specifically that of integrin subunit alpha 2, previously shown to be up-regulated by EGF/TGF-alpha. These results suggest that IL-1 alpha stimulates keratinocyte migration on collagen via a mechanism distinct from that of EGF/TGF-alpha.
Chen
J D
JD
Department of Dermatology, Northwestern University School of Medicine, Chicago, IL 60611, USA.
Lapiere
J C
JC
Sauder
D N
DN
Peavey
C
C
Woodley
D T
DT
D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000648:ultrastructure; D016207:Cytokines / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000502:physiology*; D005353:Fibronectins / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D007231:Infant, Newborn; D016023:Integrins / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D016207:Cytokines; D005353:Fibronectins; D016023:Integrins; D007375:Interleukin-1; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D003094:Collagen