MCP-1 protects mice in lethal endotoxemia.
The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study, we assessed the role of monocyte chemoattractant protein-1 (MCP-1) as a mediator of sepsis in endotoxin-challenged mice. Intraperitoneal administration of LPS to CD-1 mice induced a substantial time-dependent increase in MCP-1 in plasma, lung, and liver. The passive immunization of mice with rabbit antimurine MCP-1 antiserum 2 h before endotoxin administration resulted in a striking increase in LPS-induced mortality from 10% in control animals to 65% in anti-MCP-1-treated animals. Importantly, the administration of anti-MCP-1 antibodies to endotoxin-challenged mice resulted in increases in peak TNF-alpha and IL-12 levels, and also in a trend toward decreased serum levels of IL-10. Conversely, the administration of recombinant murine MCP-1 intraperitoneally significantly protected mice from endotoxin-induced lethality, and resulted in an increase in IL-10 levels, a decrease in IL-12 levels, and a trend toward decreased levels of TNF. In conclusion, our findings indicate that MCP-1 is a protective cytokine expressed in murine endotoxemia, and does so by shifting the balance in favor of antiinflammatory cytokine expression in endotoxin-challenged animals.
Zisman
D A
DA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA.
Kunkel
S L
SL
Strieter
R M
RM
Tsai
W C
WC
Bucknell
K
K
Wilkowski
J
J
Standiford
T J
TJ
D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use; D019446:Endotoxemia / Q000401:mortality / Q000517:prevention & control*; D005260:Female; D007116:Immunization, Passive; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D007700:Kinetics; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12