Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae.
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 gamma (IFN-gamma), 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-gamma, IL-17, or IL-17F responses to infection, whereas p35-/- mice show normal IL-17 and IL-17F induction but reduced IFN-gamma. 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 (10(3) CFU), despite normal IFN-gamma 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-gamma 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-gamma expression and the latter of which is required for IL-17 production.
Happel
Kyle I
KI
Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Dubin
Patricia J
PJ
Zheng
Mingquan
M
Ghilardi
Nico
N
Lockhart
Christie
C
Quinton
Lee J
LJ
Odden
Anthony R
AR
Shellito
Judd E
JE
Bagby
Gregory J
GJ
Nelson
Steve
S
Kolls
Jay K
JK
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007710:Klebsiella Infections / Q000276:immunology* / Q000517:prevention & control; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism
C508841:Il23a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma