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.