Staphylococcus aureus and lipopolysaccharide induce homologous tolerance but heterologous priming:: Role of interferon-γ

Lipopolysaccharide (LIPS), the gram-negative bacterial cell wall component, induces tolerance to a secondary challenge of LIPS in macrophages (MPhi) as evidenced by reduced inflammatory mediator production. However, it is uncertain if heat-killed (HK) gram-positive bacteria Staphylococcus aureus (Sa) can induce a similar tolerance and alter responses to LPS. We hypothesized that HKSa induces homologous tolerance and cross tolerance to LPS stimulation in human promonocytic THP-1 cells. We measured TNF-alpha, TxB(2), and IFN-gamma production and the phosphorylation of p38, JNK, and ERK-1/2 in human promonocytic THP-1 cells. HKSa (10 mug/mL) significantly stimulated naive (nonpretreated) cell TNF-alpha (P < 0.05) and TxB(2) production (P < 0.05). However, HKSa-pretreated cells challenged secondarily with HKSa (10 mug/mL) exhibited a decrease in the production of TNF-alpha (89 +/- 5%, P < 0.05) and TxB(2) (85 +/- 3%, P < 0.05) compared with HKSa-stimulated naive cells. By contrast, secondary LIPS challenge of HKSa-pretreated cells augmented TNF-alpha (41 +/- 3%, P < 0.05) and TxB(2) (42 +/- 6%, P < 0.05) compared with LPS-stimulated naive cells. In naive cells, HKSa and LPS stimulation also significantly phosphorylated the mitogen-activated kinases (MAPKs) p38, JNK, and ERK-1/2 (P < 0.005) compared with basal levels. HKSa and LPS induced homologous tolerance as evidenced by the down-regulation of the three MAPK (P < 0.05), thus paralleling data on mediator production. HKSa-pretreated cells' priming responses to LIPS correlated with augmented phosphorylation of JNK and p38 (P < 0.05), whereas ERK-1/2 phosphorylation remained down-regulated. In contrast to TNF-alpha and TxB(2) Production, HKSa-induced IFN-gamma was up-regulated (26 +/- 5%) in HKSa-pretreated cells compared with HKSa-stimulated naive cells.IFN-gamma antibody exhibited reversed priming in HKSa-pretreated cells as evidenced by a reduction in TNF-alpha. Exogenous human IFN-gamma- (1 mug/mL) and HKSa-pretreated cells secondarily stimulated with HKSa did not prevent the induction of tolerance. In contrast, exogenous IFN-gamma, pretreatment prevented the induction of LPS homologous tolerance resulting in an increase in TNF-alpha production. The data demonstrate that HKSa induces homologous tolerance but causes priming to LIPS.