The Journal of Experimental Medicine
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Published online 12 September 2005 doi:10.1084/jem.20050193
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 6, 761-769
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ARTICLE

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

Kyle I. Happel1,2, Patricia J. Dubin4, Mingquan Zheng4, Nico Ghilardi5, Christie Lockhart4, Lee J. Quinton2,3, Anthony R. Odden2, Judd E. Shellito1,2,3, Gregory J. Bagby2,3, Steve Nelson1,2,4, and Jay K. Kolls4

1 Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112
2 Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112
3 Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112
4 University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213
5 Genentech, South San Francisco, CA 94080

CORRESPONDENCE Jay Kolls: jay.kolls{at}chp.edu

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 (103 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.

Abbreviations used: AM, alveolar macrophages; BAL, bronchoalveolar lavage; G-CSF, granuloctye CSF; KC, keratinocyte chemoattractant; LIX, LPS- induced C-X-C chemokine; mDC, myeloid DC; MIP-2, macrophage inflammatory protein 2; mRNA, messenger RNA; pDC, plasmacytoid DC; rRNA, ribosomal RNA.

K.I. Happel, P.J. Dubin, and M. Zheng contributed equally to this work.


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