Endotoxin-induced cross-tolerance to Gram-positive sepsis

Abstract

The manifestations of Gram-positive sepsis and Gram-negative sepsis share some common clinical features suggesting common pathways of activation. The goal of this study was to assess whether lipopolysaccharide (LPS) can produce cross-tolerance to Gram-positive sepsis induced by group B streptococcus (GBS). Thromboxane (TxB₂), tumor necrosis factor (TNFα), and nitric oxide (NO) production by in vitro LPS- and heat killed GBS-stimulated rat peritoneal macrophages were measured. Since our previous studies have demonstrated altered macrophage activation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2) in tolerance, we also examined the effect of LPS and killed GBS on ERK 1/2 activation in normal and LPS tolerant macrophages. Tolerance was induced in rats by intraperitoneal injection of Salmonella enteritidis LPS or vehicle for two consecutive days at doses of 0.1 and 0.5 mg/kg body weight. Three days after the second LPS dose, rats were injected intravenously with viable GBS (5 x l0⁹ cfu/kg) and D-galactosamine (1 g/kg). LPS tolerance significantly prolonged (P <0.05) mean survival time to severe GBS sepsis in D-galactosamine sensitized rats from 12.9 ± 1.7 h in control rats to 44.0 ± 8.9 h in tolerant rats. Peritoneal macrophages from LPS tolerant rats exhibited suppressed LPS induced in vitro TxB₂ and TNFα production (P <0.05). Tolerance also decreased in vitro heat killed GBS-induced TNFα production, but did not significantly affect TxB₂ production. NO production stimulated by LPS (10 µg/ml was not impaired in LPS tolerance; however at lower doses (0.02—1.25 µg/ml), NO production was significantly decreased (P <0.05). NO production was augmented (P <0.05) in response to stimulation with GBS (10 µg/ml) and unaltered at lower doses (0.02—1.25 µg/ml) in tolerant cells. LPS activated ERK 1/2 in control macrophages, but activation of ERK 1/2 was suppressed in LPS tolerance. GBS did not significantly affect ERK 1/2 activity in control or tolerant macrophages. Nevertheless, the selective mitogen-activated kinase (MAPK)/ERK kinase (MEK) inhibitor, PD 98059 blocked (P <0.05) both GBS- and LPS-induced TNFα and TxB₂ production, but not NO production. Thus, some level of ERK 1/2 activity appears essential for GBS- and LPS-induced macrophage activation. In conclusion, LPS tolerance induces partial cross-tolerance to Gram-positive sepsis induced lethality, and alters LPS- and GBS-induced in vitro peritoneal macrophage mediator production. This suggests common pathways of cellular activation for GBS and LPS that are altered by LPS tolerance.

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