IL-23 neutralization protects mice from Gram-negative endotoxic shock.
Excessive production of proinflammatory cytokines, including TNF-alpha, IL-1, IL-6, IL-12, and IFN-gamma is thought to contribute significantly to lethality in septic shock syndromes. IL-23 is a heterodimeric cytokine that combines the p40 subunit of IL-12 with a specific p19 subunit. Similar to IL-12, IL-23 is considered to be a key immunoregulator in the response to pathogenic organisms but its contribution to Gram-negative endotoxic shock is as yet unclear. Using an established shock model with Pseudomonas aeruginosa, we found early and sustained expression of IL-23 p19 transcripts in the spleens of mice undergoing lethal challenge with the bacterium. Administration of p19-neutralizing antibody reduced mortality in a dose-dependent fashion. Survival in P. aeruginosa-challenged mice was associated with a dramatic decrease in circulating levels of the pathogenetic cytokines, TNF-alpha and IFN-gamma. Hence, IL-23 may represent a new therapeutic target in Gram-negative endotoxic shock.
Belladonna
Maria Laura
ML
Department of Experimental Medicine and Biochemical Sciences, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. laurabell@tin.it
Vacca
Carmine
C
Volpi
Claudia
C
Giampietri
Antonio
A
Fioretti
Maria Cristina
MC
Puccetti
Paolo
P
Grohmann
Ursula
U
Campanile
Franca
F
D000818:Animals; D005260:Female; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control*; D013154:Spleen / Q000378:metabolism
D053759:Interleukin-23; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins