Cutting edge: Inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice

• Published in: The Journal of immunology (1950) Vol. 188; no. 9; pp. 4141 - 4144
• Main Authors: Wunderlich, Claudia M, Delić, Denis, Behnke, Kristina, Meryk, Andreas, Ströhle, Peter, Chaurasia, Bhagirath, Al-Quraishy, Saleh, Wunderlich, Frank, Brüning, Jens C, Wunderlich, F Thomas
• Format: Journal Article
• Language: English
• Published: United States 01.05.2012
• Subjects: Animals; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - immunology; Cytokine Receptor gp130 - pharmacology; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-6 Receptor alpha Subunit - genetics; Interleukin-6 Receptor alpha Subunit - immunology; Malaria - genetics; Malaria - immunology; Mice; Mice, Knockout; Plasmodium chabaudi; Plasmodium chabaudi - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - pharmacokinetics; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102137

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.