title: Cutting edge: Inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice.
abstract: Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα-deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα-deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.
authors.affiliation: Center of Molecular Medicine Cologne, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Institute for Genetics Cologne, Max Planck Institute for Neurological Research Cologne, D-50931 Cologne, Germany.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.forename: Denis
authors.initials: D
authors.lastname: Delić
authors.forename: Kristina
authors.initials: K
authors.lastname: Behnke
authors.forename: Andreas
authors.initials: A
authors.lastname: Meryk
authors.forename: Peter
authors.initials: P
authors.lastname: Ströhle
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Chaurasia
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Quraishy
authors.forename: Frank
authors.initials: F
authors.lastname: Wunderlich
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D053698:Interleukin-6 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008288:Malaria / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016788:Plasmodium chabaudi / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130