Human Neutrophil Lactoferrin trans-Activates the Matrix Metalloproteinase 1 Gene through Stress-activated MAPK Signaling Modules

It has been proposed that human neutrophil lactoferrin (Lf) could be involved in gene expression as a DNA-binding protein after its translocation into the nucleus. However, the molecular basis of Lf action has not been defined, and Lf-regulated target genes have not been identified. We report here that overexpressed Lf functions as a specific trans-activator of matrix metalloproteinase 1 (MMP1) gene, and that induction of this AP-1-responsive gene is mediated via the stress-activated MAPK signaling modules. Transactivation of the MMP1 promoter by overexpressed Lf requires the presence of an AP-1 binding site. In gel shift experiments, Lf did not interact directly with AP-1-containing fragments of the MMP1 promoter. However, nuclear extracts from Lf-expressing cells contained increased levels of proteins that bound to AP-1 elements. This Lf-induced AP-1 DNA binding activity was reduced by a p38 MAPK inhibitor. Inhibitors of the MEK kinases had little effect on Lf-induced AP-1. However, expression of dominant-negative MKK4 or JNK1 inhibited Lf-induced gene expression. The JNK activity stimulated by Lf correlates with the enhanced AP-1 binding ability. These findings demonstrate that the Lf-induced activation of AP-1 is mediated via JNK and p38 MAPK pathways.