The acute-phase protein α1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts

Abstract

Transferrin (Tf) is required for proliferation of most cells, because cellular iron uptake is mainly mediated by binding of Tf to its specific cell surface receptors (TfR). The acute-phase protein α1-antitrypsin (α1-AT) completely inhibits binding of diferric Tf to TfRs on human skin fibroblasts in a dose-dependent fashion. The inhibition is competitive as proved in equilibrium saturation binding and kinetic studies. In saturation binding experiments α1-AT apparently increased the dissociation constant ( K D), but did not change the maximal density of binding sites ( B max). As shown in kinetic studies, this reduction of the affinity of Tf to its receptor caused by α1-AT was due to a decrease of the association rate constant ( k+1), whereas the dissociation rate constant ( k−1) remained unchanged. Furthermore, α1-AT almost completely prevented internalization of the Tf–TfR complex. These interactions demonstrated biological implication, as α1-AT reduced the proliferation of human fibroblasts up to maximal 30% of control. The inhibitory potency of α1-AT was already seen in physiologic concentrations; the maximal effect, however, was achieved at concentrations above the normal range, which are attained in the course of inflammation and infection. Therefore, we suppose that α1-AT as an endogenous factor modulates the complex mechanism of fibrogenesis not only by its known antiproteolytic function but also by inhibiting the proliferation of fibroblasts.