TNF alpha induces expression of transcription factors c-fos, Egr-1, and Ets-1 in vascular lesions through extracellular signal-regulated kinases 1/2

Migration, proliferation and differentiation of vascular smooth muscle cell s (VSMC) and macrophages are important pathological responses that contribu te to the development and progression of vascular lesions. Cytokines such a s TNF alpha are present at sites of vascular injury and regulate a variety of cellular functions of inflammatory cells and VSMC. Cell migration, proli feration and differentiation require de novo gene transcription resulting f rom extracellular signals being transduced to the nucleus, where multiple g enes are regulated to participate in lesion formation. In VSMC and macropha ges, TNFa induces activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2), which transmit signals from the cytosol to the nucleus. Pote ntial nuclear targets of TNF alpha -activated ERK 1/2 include the transcrip tion factors Ets-1, Egr-1, and c-fos, which are known to regulate cellular growth, differentiation, and migration. The aim of this study was to invest igate the expression of the transcription factors Ets-1, Egr-1 and c-fos in different types of vascular lesions, their regulation by TNF alpha and the role of ERK 1/2 in these signaling events. Atherosclerotic lesions from fr uctose-fed LDL-receptor deficient mice and neointimal lesions from rat aort ae 2 weeks post balloon injury demonstrated the presence and colocalization of TNF alpha, phosphorylated and activated ERK 1/2, and transcription fact ors Ets-1, Egr-1 and c-fos. Neointimal lesions consisted primarily of VSMC, whereas atherosclerotic lesions predominantly contained macrophages. In cu ltured rat aortic VSMC, TNF alpha (100 U/ml) stimulated a rapid and transie nt expression of Ets-1, Egr-1 and c-fos with a maximal induction I h after stimulation. In cultured RAW 264.7 mouse macrophages, TNF alpha similarly i nduced the expression of Ets-1, Egr-1, and c-fos. Induction of these transc ription factors was mediated via ERK 1/2 activation, since the ERK 1/2-path way inhibitor PD98059 (10-30 muM) significantly inhibited their TNF alpha - induced expression. TNF alpha induced ERK 1/2 activation in both cell types . These findings underscore the importance of the ERK 1/2 pathway in the ex pression of TNF alpha -regulated transcription factors, which may participa te in different forms of vascular lesion formation. (C) 2001 Elsevier Scien ce Ireland Ltd. All rights reserved.