Resistance to lipopolysaccharide mediated by the Yersinia pestis V antigen-polyhistidine fusion peptide: Amplification of interleukin-10

We previously showed that injection of homogenous staphylococcal protein A-V antigen fusion peptide into mice delayed allograft rejection and suppressed the major proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) associated with generation of protective granulomas. This study was undertaken to determine if V antigen could prevent endotoxic shock, known to be mediated by excessive production of certain proinflammatory cytokines. After treatment with 50 mu g of homogeneous V antigen-polyhistidine fusion peptide (V-b), the 50% lethal dose of purified lipopolysaccharide (LPS) in BALR/c mice immediately rose from 63 mu g (normal controls) to 318 mu g, fell to near baseline (71 mu g) in 6 hr, and then slowly rose to a maximum of 566 mu g at 45 h before again returning to normal. Injected V-h alone (50 mu g) promptly induced the anti-inflammatory cytokine interleukin-10 (IL-IO) as well as modest levels of TNF-alpha (an inducer of IL-10) in spleen, Concomitant injection of V-h and an otherwise lethal dose of LPS (200 mu g) dramatically decreased levels of TNF-alpha and IFN-gamma in the spleen and peritoneal lavage fluid as compared to values determined for LPS alone, These results would be expected if V antigen directly up-regulated a 10 that is reported to generally down-regulate proinflammatory cytokines, Mice receiving 200 mu g of LPS 48 h after injection of V-h exhibited patterns of cytokine synthesis similar to those observed in endotoxin-tolerant mice, a condition also reported to be mediated by IL-IO, These findings suggest that V antigen serves as a virulence factor by amplifying IL-10, thereby repressing proinflammatory cytokines required for expression of cell-mediated immunity.