Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Cell Line; Cells, Cultured; Cytokines; Early Growth Response Protein 1; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Myeloid Differentiation Factor 88; Streptococcus agalactiae; Transcription Factor AP-1; ets-Domain Protein Elk-1; p38 Mitogen-Activated Protein Kinases
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-kappaB. 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.
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Citation: Infect Immun. 2009 Jun;77(6):2474-81. Epub 2009 Mar 30. Link to article on publisher's site
Kenzel, Sybille; Santos-Sierra, Sandra; Deshmukh, Sachin D.; Moeller, Inga; Ergin, Bilge; Fitzgerald, Katherine A.; Lien, Egil; Akira, Shizuo; Golenbock, Douglas T.; and Henneke, Phillip, "Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus" (2009). Infectious Diseases and Immunology Publications and Presentations. Paper 64.