Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

KI Happel, PJ Dubin, M Zheng, N Ghilardi… - The Journal of …, 2005 - rupress.org
KI Happel, PJ Dubin, M Zheng, N Ghilardi, C Lockhart, LJ Quinton, AR Odden, JE Shellito
The Journal of experimental medicine, 2005rupress.org
Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12
but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon γ (IFN-γ), and
IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae–
pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23–dependent
manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown.
We show that IL-12/23 p40–deficient mice are exquisitely sensitive to intrapulmonary K …
Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon γ (IFN-γ), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae–pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23–dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40–deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19/, IL-17R/, and IL-12 p35/ mice also show increased susceptibility to infection. p40/ mice fail to generate pulmonary IFN-γ, IL-17, or IL-17F responses to infection, whereas p35/ mice show normal IL-17 and IL-17F induction but reduced IFN-γ. Lung IL-17 and IL-17F production in p19/ mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria (103 CFU), despite normal IFN-γ induction. Administration of IL-17 restored bacterial control in p19/ mice and to a lesser degree in p40/ mice, suggesting an additional host defense requirement for IFN-γ in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-γ expression and the latter of which is required for IL-17 production.
rupress.org