Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy.
OBJECTIVE
Sepsis remains a serious clinical problem, and multiple attempts at blocking inflammation have failed to decrease mortality rate. Interleukin-18 has been demonstrated to be an important component of the innate immune response to bacterial infections.


METHODS
Previous work demonstrated that elevated plasma concentrations of interleukin-6 obtained in the first 6 hrs of sepsis predict a worse outcome. Mice were subjected to cecal ligation and puncture and, on the basis of the plasma concentration of interleukin-6, were randomized to receive either interleukin-18 binding protein or vehicle approximately 8 hrs after the onset of sepsis.


METHODS
University research laboratory.


METHODS
Adult, female BALB/c mice.


METHODS
We sought to determine the role of interleukin-18 in sepsis by blocking its biological activity with the interleukin-18 binding protein in the murine model of sepsis induced by cecal ligation and puncture.


RESULTS
In this study, elevated plasma concentrations of interleukin-6 were associated with a worse outcome. Treatment with interleukin-18 binding protein decreased inflammation as determined by lower concentrations of plasma interleukin-6 obtained 48 hrs after the onset of sepsis. In mice with increased risk of dying, interleukin-18 binding protein slightly decreased mortality rate. However, in those mice with a predicted low mortality rate, interleukin-18 binding protein significantly increased mortality rate.


CONCLUSIONS
In this study, mice at low risk of death due to sepsis had decreased survival when treated with interleukin-18 binding protein. These results have potential implications for the use of interleukin-18 binding protein for treatment of chronic inflammatory conditions since it may place the host at increased risk of infectious complications.
Remick
Daniel G
DG
Department of Pathology, University of Michigan, Ann Arbor, 48109-0602, USA. remickd@umich.edu
Bolgos
Gerald E
GE
Siddiqui
Javed
J
D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000097:blood*; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000097:blood*; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D016019:Survival Analysis
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C118370:interleukin-18 binding protein