Group B streptococcal beta-hemolysin induces nitric oxide production in murine macrophages.
Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. To examine the role of the GBS beta-hemolysin in NO production, the murine macrophage line RAW 264. 7 was exposed to a wild-type (WT) GBS isolate and to hyperhemolytic (HH) and nonhemolytic (NH) transposon mutants derived from that isolate. After activation of macrophages by the WT strain, the HH mutant, or cell-free extracts of beta-hemolysin, nitrite release into the supernatant increased >10-fold and inducible NO synthase (iNOS) levels in cell lysates increased up to 10-fold compared with treatment with the NH mutant or extracts from that mutant. Hemolysin-induced NO production was dependent on protein tyrosine kinases and NF-kappaB, but not on extracellular signal-related kinase-1/2-mitogen-activated kinases or protein kinase A. These results indicate that GBS beta-hemolysin induces murine macrophage iNOS via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation.
Ring
A
A
Department of Internal Medicine IV, Ruprecht-Karls-University, Heidelberg, Germany.
Braun
J S
JS
Nizet
V
V
Stremmel
W
W
Shenep
J L
JL
D000818:Animals; D001426:Bacterial Proteins; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D006460:Hemolysin Proteins / Q000494:pharmacology*; D006461:Hemolysis; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D001426:Bacterial Proteins; D006460:Hemolysin Proteins; D009573:Nitrites; C071495:streptococcal group B hemolysin; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse