In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese

Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.