c-Jun kinase is a critical signaling molecule in a neonatal model of group B streptococcal sepsis.
Group B streptococcus (GBS) is the major cause of sepsis in newborn infants. In vitro, inactivated GBS stimulates macrophages to produce inflammatory proteins via the TLR adapter protein MyD88. Furthermore, inflammatory cytokine release in response to GBS greatly exceeds that following stimulation with pneumococci. In this study, we attempted to unravel signaling events that are involved in GBS-, but not Streptococcus pneumoniae-stimulated phagocytes to identify molecular targets for adjunctive sepsis therapy. We found that inactivated GBS and S. pneumoniae differed in the activation of the MAPK JNK, but not IkappaB kinase. Furthermore, JNK was essential for the transcriptional activation of inflammatory cytokine genes in response to GBS. Inhibition of JNK by the anthrapyrazolone SP600125 abrogated GBS-induced cytokine formation via an AP-1- and NF-kappaB-dependent mechanism without impairing antibacterial properties such as phagocytosis of GBS and the formation of intracellular oxidative species. In contrast, inhibition of the MAPK p38 impaired both antibacterial processes. In a neonatal mouse model of GBS sepsis SP600125 inhibited the inflammatory response and improved survival. In conclusion, JNK plays a major role in the inflammatory, but not in the direct antibacterial response to inactivated GBS, and may thus serve as a rational target for an adjunctive GBS sepsis therapy.
Children's Hospital, Albert-Ludwigs University, Freiburg, Germany.
Sybille
S
Kenzel
Guiseppe
G
Mancuso
Richard
R
Malley
Guiseppe
G
Teti
Douglas T
DT
Golenbock
Philipp
P
Henneke
D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D051550:I-kappa B Kinase / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology / Q000401:mortality; D013290:Streptococcal Infections / Q000201:enzymology*; D013292:Streptococcus agalactiae / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000873:Anthracenes; D016207:Cytokines; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases