title: Endotoxin tolerance: independent regulation of interleukin-1 and tumor necrosis factor expression.
abstract: The injection of lethal or sublethal doses of bacterial lipopolysaccharide (LPS) into mice results in transient increases in both serum tumor necrosis factor (TNF) and interleukin-1 (IL-1). The peak in serum TNF was detected prior to maximal elevation in endogenous corticosterone and was no longer apparent 3 to 4 h post-LPS injection, a point at which corticosterone and IL-1 levels had significantly increased. The initial increase in serum IL-1 may, in part, be modulated by the preceding TNF peak, as pretreating animals with a monoclonal antibody against murine TNF resulted in a significant decrease in IL-1 levels 3 h post-LPS injection. A second injection of LPS at 20 h failed to result in a secondary TNF peak, suggesting an endotoxin-tolerant state. However, in contrast to TNF, significant increases in serum IL-1 were detected in the endotoxin-tolerant animals following a repeated LPS stimulus. This secondary increase in IL-1 occurred despite the elevation in serum corticosterone. While peritoneal macrophages from endotoxin-tolerant mice demonstrated only a modest 10 to 15% increase in TNF and IL-1 mRNA relative to the levels after the primary 1-h LPS stimulus, a secondary increase in IL-1 but not TNF mRNA in the spleen was apparent following a second LPS injection. The spleen, however, was not essential for the increase in serum IL-1, as endotoxin-tolerant splenectomized mice had comparable increases in IL-1 following a repeated LPS stimulus. These results demonstrate the differential regulation of IL-1 and TNF in vivo during endotoxin tolerance.
authors.affiliation: Department of Immunology, Lilly Research Laboratories, Indianapolis, Indiana 46285.
authors.forename: S H
authors.initials: SH
authors.lastname: Zuckerman
authors.forename: G F
authors.initials: GF
authors.lastname: Evans
authors.forename: L D
authors.initials: LD
authors.lastname: Butler
mesh_terms: D000818:Animals; D002460:Cell Line; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D007106:Immune Sera; D007108:Immune Tolerance; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D007106:Immune Sera; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D003345:Corticosterone