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Infection and Immunity, June 2009, p. 2474-2481, Vol. 77, No. 6
0019-9567/09/$08.00+0 doi:10.1128/IAI.01343-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Role of p38 and Early Growth Response Factor 1 in the Macrophage Response to Group B Streptococcus
Sybille Kenzel,1,2
Sandra Santos-Sierra,1
Sachin D. Deshmukh,1
Inga Moeller,1
Bilge Ergin,5
Katherine A. Fitzgerald,3
Egil Lien,3
Shizuo Akira,4
Douglas T. Golenbock,3 and
Philipp Henneke1,2*
Center for Pediatric and Adolescent Medicine, University Medical Center Freiburg, Mathildenstr. 1, 79106 Freiburg, Germany,1 Center of Chronic Immunodeficiency, University Medical Center Freiburg, Mathildenstr. 1, 79106 Freiburg, Germany,2 Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605,3 Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Osaka 565-0871, Japan,4 Institut for Cell Biology, University of Tuebingen, Department of Molecular Biology Auf der Morgenstelle 15, 72076 Tuebingen, Germany5
Received 3 November 2008/ Returned for modification 23 December 2008/ Accepted 18 March 2009
Group B streptococcus (GBS), the most frequent single isolate in neonatal sepsis and meningitis, potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88). However, events parallel to and downstream of MyD88 that instruct the macrophage response are incompletely understood. In this study, we found that only MyD88, not the Toll-like receptor (TLR) adapter proteins MAL/TIRAP, TRIF, and TRAM, essentially mediates the cytokine (tumor necrosis factor [TNF] and interleukin-6) and chemokine (RANTES) responses to whole GBS organisms, although MAL, TRIF, and TRAM have been shown to mediate the responses to substructures in other gram-positive and gram-negative bacteria. GBS-induced, MyD88-dependent phosphorylation of the mitogen-activated protein kinase p38 activated the transcription factor AP-1 and early growth response factor 1 (Egr-1) but not NF-
B. Furthermore, phosphorylation of Ets-like molecule 1 (Elk-1) was mediated by p38. However, in contrast to Egr-1 and AP-1, Elk-1 was dispensable for transcriptional activation of TNF by GBS organisms. Studies of macrophages from Elk-1-deficient mice revealed that Elk-1 was furthermore nonessential for the TNF responses to purified TLR2 and TLR4 agonists, which was in notable contrast to what was revealed in studies employing in vitro expression systems. In conclusion, MyD88, p38, and Egr-1, but not Elk-1, essentially mediate the inflammatory cytokine response to GBS organisms.
* Corresponding author. Mailing address: Zentrum für Kinder- und Jugendmedizin, Centrum für Chronische Immundefizienz (CCI), Mathildenstr. 1, D-79106 Freiburg, Germany. Phone: 49-761-270-4301. Fax: 49-761-270-7760. E-mail: philipp.henneke{at}uniklinik-freiburg.de
Published ahead of print on 30 March 2009.
Infection and Immunity, June 2009, p. 2474-2481, Vol. 77, No. 6
0019-9567/09/$08.00+0 doi:10.1128/IAI.01343-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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