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Infection and Immunity, October 2005, p. 6499-6507, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6499-6507.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation and Mitogen-Activated Protein Kinase Regulation of Transcription Factors Ets and NF-B in Mycobacterium-Infected Macrophages and Role of These Factors in Tumor Necrosis Factor Alpha and Nitric Oxide Synthase 2 Promoter Function

Seong-Beom Lee and Jeffrey S. Schorey^*

Department of Biological Sciences, Center for Tropical Disease Research and Training, University of Notre Dame, Notre Dame, Indiana 46556

Received 8 April 2005/ Returned for modification 23 May 2005/ Accepted 17 June 2005

Previous studies have shown that primary murine macrophages infected with Mycobacterium avium produced lower levels of tumor necrosis factor alpha (TNF-) and inducible nitric oxide synthase 2 (NOS2) compared to cells infected with nonpathogenic Mycobacterium smegmatis. TNF- 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- or NOS2 promoter vector. We determined that macrophages infected with M. avium compared to M. smegmatis showed diminished TNF- and NOS2 promoter activity. A more pronounced difference in promoter activity was observed when only the consensus ETS and NF-B binding sites were used as promoters. Mutational analysis of the ETS and NF-B binding sites present on the TNF- and NOS2 promoters, respectively, showed that these sites were essential for a functional promoter. Moreover, the Ets/Elk but not the NF-B transcriptional response was dependent on ERK1/2. This correlated with the requirement for ERK1/2 in TNF- but not NOS2 promoter activity. Our data indicate that the increased Ets/Elk and NF-B promoter activities associated with M. smegmatis-infected macrophages are responsible, at least in part, for the increased TNF- and NOS2 production observed in these infected cells and that ERK1/2 is required for Ets/Elk activity and full TNF- production.

Editor: W. A. Petri, Jr.

Present address: Institute of Hansen's Disease, College of Medicine, The Catholic University of Korea, 505-Manpo-dong, Socho-gu, Seoul, 137-701 Korea.

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