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 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.
Nedialkov
Y A
YA
Department of Microbiology, Michigan State University, East Lansing 48824-1101, USA.
Motin
V L
VL
Brubaker
R R
RR
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage* / Q000235:genetics; D005260:Female; D006639:Histidine; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000008:administration & dosage* / Q000235:genetics; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D012772:Shock, Septic / Q000517:prevention & control*; D015010:Yersinia pestis / Q000378:metabolism*
D000942:Antigens, Bacterial; C043908:LcrV protein, Yersinia; D008070:Lipopolysaccharides; D010455:Peptides; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; C033223:polyhistidine; D006639:Histidine