Activation and Mitogen-Activated Protein Kinase Regulation of Transcription Factors Ets and NF-[kappa]B in Mycobacterium-Infected Macrophages and Role of These Factors in Tumor Necrosis Factor Alpha and Nitric Oxide Synthase 2 Promoter Function
2005
Lee, Seong-Beom | Schorey, Jeffrey S.
Previous studies have shown that primary murine macrophages infected with Mycobacterium avium produced lower levels of tumor necrosis factor alpha (TNF-[alpha]) and inducible nitric oxide synthase 2 (NOS2) compared to cells infected with nonpathogenic Mycobacterium smegmatis. TNF-[alpha] and NOS2 levels correlated with and were dependent on the activation of mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). To define the macrophage transcriptional responses dependent on ERK1/2 activation following a mycobacterial infection, we used RAW 264.7 cells transfected with a TNF-[alpha] or NOS2 promoter vector. We determined that macrophages infected with M. avium compared to M. smegmatis showed diminished TNF-[alpha] and NOS2 promoter activity. A more pronounced difference in promoter activity was observed when only the consensus ETS and NF-[kappa]B binding sites were used as promoters. Mutational analysis of the ETS and NF-[kappa]B binding sites present on the TNF-[alpha] and NOS2 promoters, respectively, showed that these sites were essential for a functional promoter. Moreover, the Ets/Elk but not the NF-[kappa]B transcriptional response was dependent on ERK1/2. This correlated with the requirement for ERK1/2 in TNF-[alpha] but not NOS2 promoter activity. Our data indicate that the increased Ets/Elk and NF-[kappa]B promoter activities associated with M.smegmatis-infected macrophages are responsible, at least in part, for the increased TNF-[alpha] and NOS2 production observed in theseinfected cells and that ERK1/2 is required for Ets/Elk activity and full TNF-[alpha] production.
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