Administration of interleukin-10 at the time of priming protects Corynebacterium parvum-primed mice against LPS- and TNF-alpha-induced lethality.
Several laboratories have described the protective effects of interleukin-10 (IL-10) in mouse models of lethal endotoxemia. In most of these experiments, protection was observed in normal mice that were given a lethal dose of LPS. However, we failed to observe protection with IL-10 in LPS-challenged mice that had been primed with Corynebacterium parvum (Proprionibacterium acnes). We have extended our studies with IL-10 in C. parvum-primed mice and in some cases have observed protection that appears to depend on the strength of the sensitization to C. parvum. When IL-10 was administered to mice at the time of priming, it was particularly effective in blocking sensitization, as evidenced by the inability of treated mice to mount a strong inflammatory cytokine response when subsequently challenged with LPS. Following such treatment with IL-10, C. parvum-primed mice were also protected from a subsequent lethal challenge with rMuTNF-alpha. In addition, the mice were protected against LPS- and TNF-alpha-induced lethality with a single dose of an anti-TNF-alpha or anti-IFN-gamma mAb given at the time of priming. Our results suggest that TNF-alpha and IFN-gamma are produced early after priming with C. parvum and are at least partly responsible for the enhanced sensitivity of the mice to LPS and TNF-alpha. IL-10 affords protection to the mice because of its ability to block the C. parvum-induced TNF-alpha and IFN-gamma responses.
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
S R
SR
Smith
C
C
Terminelli
G
G
Denhardt
S
S
Narula
G J
GJ
Thorbecke
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000517:prevention & control; D006801:Humans; D007114:Immunization; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011425:Propionibacterium acnes / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013163:Splenomegaly / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000633:toxicity
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10