title: IL-23 neutralization protects mice from Gram-negative endotoxic shock.
abstract: 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.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. laurabell@tin.it
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Belladonna
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Antonio
authors.initials: A
authors.lastname: Giampietri
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Franca
authors.initials: F
authors.lastname: Campanile
mesh_terms: 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
chemical_list: D053759:Interleukin-23; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins