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Infect. Immun., Apr 1997, 1196-1203, Vol 65, No. 4
Copyright © 1997, American Society for Microbiology

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

YA Nedialkov, VL Motin and RR Brubaker
Department of Microbiology, Michigan State University, East Lansing 48824-1101, USA.

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 microg of homogeneous V antigen- polyhistidine fusion peptide (Vh), the 50% lethal dose of purified lipopolysaccharide (LPS) in BALB/c mice immediately rose from 63 microg (normal controls) to 318 microg, fell to near baseline (71 microg) in 6 h, and then slowly rose to a maximum of 566 microg at 48 h before again returning to normal. Injected Vh alone (50 microg) promptly induced the anti-inflammatory cytokine interleukin-10 (IL-10) as well as modest levels of TNF-alpha (an inducer of IL-10) in spleen. Concomitant injection of Vh and an otherwise lethal dose of LPS (200 microg) 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 IL-10 that is reported to generally down-regulate proinflammatory cytokines. Mice receiving 200 microg of LPS 48 h after injection of Vh exhibited patterns of cytokine synthesis similar to those observed in endotoxin-tolerant mice, a condition also reported to be mediated by IL-10. 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.


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