Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock.
BACKGROUND
Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood.


OBJECTIVE
To clarify the long disputed hierarchical contribution of several central inflammatory mediators (IL-1β, IL-18, caspase [CASP] 7, CASP1, and CASP11) in septic shock and to explore their therapeutic potential.


METHODS
LPS- and tumor necrosis factor (TNF)-induced lethal shock, and cecal ligation and puncture (CLP) were performed in genetically or pharmacologically targeted mice. Body temperature and survival were monitored closely, and plasma was analyzed for several markers of cellular disintegration and inflammation.


RESULTS
Interestingly, deficiency of both IL-1β and IL-18 additively prevented LPS-induced mortality. The detrimental role of IL-1β and IL-18 was confirmed in mice subjected to a lethal dose of TNF, or to a lethal CLP procedure. Although their upstream activator, CASP1, and its amplifier, CASP11, are considered potential therapeutic targets because of their crucial involvement in endotoxin-induced toxicity, CASP11- or CASP1/11-deficient mice were not, or hardly, protected against a lethal TNF or CLP challenge. In line with our results obtained in genetically deficient mice, only the combined neutralization of IL-1 and IL-18, using the IL-1 receptor antagonist anakinra and anti-IL-18 antibodies, conferred complete protection against endotoxin-induced lethality.


CONCLUSIONS
Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.
1 Inflammation Research Center, VIB, Ghent, Belgium.
Tom
T
Vanden Berghe
Dieter
D
Demon
Pieter
P
Bogaert
Benjamin
B
Vandendriessche
Alain
A
Goethals
Bart
B
Depuydt
Marnik
M
Vuylsteke
Ria
R
Roelandt
Elien
E
Van Wonterghem
Jill
J
Vandenbroecke
Sze Men
SM
Choi
Evelyn
E
Meyer
Stefan
S
Krautwald
Wim
W
Declercq
Nozomi
N
Takahashi
Anje
A
Cauwels
Peter
P
Vandenabeele
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001323:Autoantibodies / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D020170:Caspase 1 / Q000097:blood / Q000172:deficiency; D053179:Caspase 7 / Q000097:blood / Q000172:deficiency; D020169:Caspases / Q000097:blood / Q000172:deficiency; D053471:Caspases, Initiator; D002432:Cecum / Q000601:surgery; D004359:Drug Therapy, Combination; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha
D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D015415:Biomarkers; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; C101136:Casp4 protein, mouse; C505524:Casp7 protein, mouse; D053179:Caspase 7; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1