Recent studies indicate a potential role for Fra-1, a heterodimeric partner of AP1, in toxicant-induced epithelial injury, repair, and cellular transformation. Here, we have investigated the effects of diesel exhaust particles (DEP) on fra-1 expression in C10 cells, a nonmalignant murine alveolar type II-like epithelial cell line. DEP markedly up-regulated fra-1, but not fra-2, expression. The increase in fra-1 mRNA expression correlated well with its protein and DNA binding activity. Electrophoretic mobility shift assay with antibodies specific to each of the other AP1 family members revealed a predominant presence of Jun-B and Jun-D in the AP1 complex. Interestingly, DEP did not alter Jun-B and Jun-D protein levels. Transcriptional analysis revealed that fra-1 induction is regulated in part at the transcriptional level. The -379 to +32 bp 5'-flanking region mediated this induction. Furthermore, inhibitors of ERK1/2, JNK1 and p38 mitogen-activated protein kinases (MAPKs) significantly suppressed DEP-stimulated fra-1 promoter activity and expression suggesting their involvement in the induction process. Consistent with this finding, DEP stimulated phosphorylation of ERK1/2, JNK1 and p38 MAPKs with a distinct activation pattern. Overexpression of Fra-1 down-regulated both basal and c-Jun enhanced AP1 transcriptional activity. It had a similar effect on basal and Nrf2-enhanced ARE-mediated reporter gene expression. In contrast, Fra-1 had the opposite effect on MMP-9 promoter activity. In particular, it bound to the functional TRE sequence of the MMP-9 promoter after DEP stimulation. Consistent with this result, DEP also markedly up-regulated MMP-9 promoter activity. Collectively, these findings suggest that fra-1 induction by DEP may play a role in selectively regulating gene expression involved in alveolar epithelial cell injury and repair.