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Infection and Immunity, January 2007, p. 270-277, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01412-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase Controls NF-{kappa}B Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response to Borrelia burgdorferi Antigens{triangledown}

Chris M. Olson,1,{dagger} Michael N. Hedrick,2,{dagger},{ddagger} Hooman Izadi,1 Tonya C. Bates,1,2 Elias R. Olivera,1 and Juan Anguita1,2*

Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, Massachusetts 01003,1 Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 282232

Received 1 September 2006/ Returned for modification 29 September 2006/ Accepted 16 October 2006

The interaction of Borrelia burgdorferi, the causative agent of Lyme borreliosis, with phagocytic cells induces the activation of NF-{kappa}B and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-{alpha}). B. burgdorferi-induced TNF-{alpha} production is also dependent on the activation of p38 mitogen-activated protein (MAP) kinase. The specific contribution of these signaling pathways to the response of phagocytic cells to the spirochete and the molecular mechanisms underlying this response remain unresolved. We now show that p38 MAP kinase activity regulates the transcriptional activation of NF-{kappa}B in response to spirochetal lysate stimulation of phagocytic cells. The regulation occurs at the nuclear level and is independent of the translocation of the transcription factor to the nucleus or its capacity to bind to specific DNA target sequences. In RAW264.7 cells, p38{alpha} MAP kinase regulates the phosphorylation of NF-{kappa}B RelA. p38 MAP kinase phosphorylates the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 in turn phosphorylates the transcriptionally active subunit of NF-{kappa}B, RelA. The repression of MSK1 expression with small interfering RNA results in reduced RelA phosphorylation and a significant decrease in the production of TNF-{alpha} in response to B. burgdorferi lysates. Overall, these results clarify the contribution of the signaling pathways that are activated in response to the interaction of spirochetes with phagocytic cells to TNF-{alpha} production. Our results situate p38 MAP kinase activity as a central regulator of the phagocytic proinflammatory response through MSK1-mediated transcriptional activation of the transcription factor NF-{kappa}B.

* Corresponding author. Mailing address: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, 103 Paige Lab., 161 Holdsworth Way, Amherst, MA 01003. Phone: (413) 577-3317. Fax: (413) 545-6326. E-mail: janguita{at}vasci.umass.edu.

{triangledown} Published ahead of print on 30 October 2006.

Editor: D. L. Burns

{dagger} C.M.O. and M.N.H. contributed equally to this report.

{ddagger} Present address: Inflammation Biology Section, Laboratory of Molecular Immunology, NIAID/NIH, Bethesda, MD.

Infection and Immunity, January 2007, p. 270-277, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01412-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Garrett, S., Dietzmann-Maurer, K., Song, L., Sullivan, K. E. (2008). Polarization of Primary Human Monocytes by IFN-{gamma} Induces Chromatin Changes and Recruits RNA Pol II to the TNF-{alpha} Promoter. J. Immunol. 180: 5257-5266 [Abstract] [Full Text]  


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