Rac1‐mediated H2O2 generation suppresses MMP‐9 expression via ERK

Abstract

Our previous observations demonstrate that deletion of Rac1 from cells of the myeloid lineage protects mice from asbestos‐induced pulmonary fibrosis due to attenuated H2O2 generation. To address whether this was due to increased matrix degradation, we investigated the expression of matrix metalloproteinase (MMP‐9) in Rac1 null macrophages. Compared to wild type (WT) macrophages, MMP‐9 gene expression was significantly greater in Rac1 null cells. Site directed mutagenesis of the MMP‐9 promoter revealed that SP‐1 and AP‐1 were necessary for MMP‐9 expression. As these transcription factors are activated by MAP kinases, we examined the role of ERK in Rac1‐mediated MMP‐9 gene transcription. ERK activation was dramatically increased in Rac1 null cells and transfection with dominant‐negative ERK significantly decreased MMP‐9 promoter activity. Exogenous H2O2 inhibited MMP‐9 promoter activity in Rac1 null cells whereas over expressed catalase in WT cells enhanced ERK activation and MMP‐9 expression. Thus Rac1‐mediated H2O2 production suppresses MMP‐9 expression via inhibition of ERK. In vivo, MMP‐9 mRNA was enhanced in lung macrophages of Rac1 null mice and in WT mice administered catalase after asbestos exposure. These data suggest that enhanced MMP‐9 expression attenuates, in part, the development of asbestos‐induced pulmonary fibrosis. This work was supported by NIH grant ES‐015981.