Effects of repeated injections of fibroblast-stimulating lipopeptide-1 on fever, formation of cytokines, and on the responsiveness to endotoxin in guinea-pigs.
OBJECTIVE
We investigated, whether the Toll-like receptors (TLRs)-2/6-agonist fibroblast-stimulating lipopeptide-1 (FSL-1), like the TLR-4 agonist lipopolysaccharide (LPS), induces a state of tolerance. We further tested the influence of repeated pre-treatment with FSL-1 on the animals' responsiveness to LPS.


METHODS
Abdominal temperature was recorded in unrestrained guinea-pigs with intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6) were measured with specific bioassays. We tested the effects of intra-arterial (i.a.) or intraperitoneal (i.p.) injections of 100 microg kg(-1) FSL-1, repeated five times at intervals of 3 days. The animals' responses to i.a. or i.p. injections of 10 microg kg(-1) LPS were determined another 3 days later and compared to those of naïve guinea-pigs.


RESULTS
The FSL-1-induced TNF peak was significantly attenuated starting with the third i.a. administration, while fever was unimpaired and the IL-6-peak just tended to decrease. Fever and IL-6 in response to i.a. injections of LPS were identical in both groups, while circulating TNF was higher in naïve compared to FSL-1 pre-treated animals. The effects of repeated i.p. injections of FSL-1 were more pronounced resulting in attenuation of fever as well as circulating TNF and IL-6, the strongest reduction observed after the third stimulation with FSL-1. Repeated i.p. pre-treatment with FSL-1 induced hyporesponsiveness to i.p. administration of LPS compared to naïve animals with regard to fever and especially with regard to LPS-induced formation of cytokines.


CONCLUSIONS
There is a development of tolerance to FSL-1 and cross-tolerance between FSL-1 and LPS depending on the route of administration of the respective TLR-2/6 and TLR-4 agonists.
Greis
A
A
Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Giessen, Germany.
Murgott
J
J
Gerstberger
R
R
Hübschle
T
T
Roth
J
J
D000818:Animals; D016207:Cytokines / Q000187:drug effects / Q000276:immunology*; D004075:Diglycerides / Q000008:administration & dosage / Q000276:immunology*; D005334:Fever / Q000139:chemically induced / Q000276:immunology*; D006168:Guinea Pigs; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000819:agonists / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016207:Cytokines; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009842:Oligopeptides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha