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Infection and Immunity, December 2005, p. 8226-8236, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8226-8236.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Interferon-Inducible Protein 10, but Not Monokine Induced by Gamma Interferon, Promotes Protective Type 1 Immunity in Murine Klebsiella pneumoniae Pneumonia

Xianying Zeng,2 Thomas A. Moore,2 Michael W. Newstead,2 Jane C. Deng,2 Steven L. Kunkel,1 Andrew D. Luster,3 and Theodore J. Standiford2*

Departments of Pathology,1 Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan,2 Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts3

Received 7 June 2005/ Returned for modification 21 July 2005/ Accepted 26 August 2005

CXC chemokines that lack the ELR motif, including interferon-inducible protein 10 [IP-10 (CXCL10)] and monokine induced by gamma interferon (IFN-{gamma}) [MIG (CXCL9)], have been shown to mediate the generation of type 1 immune responses. In this study, we found that intrapulmonary administration of the gram-negative bacterium Klebsiella pneumoniae resulted in the local and systemic expression of IP-10, followed sequentially by MIG expression. MIG mRNA expression in the lungs of Klebsiella-infected mice required the endogenous production of IFN-{gamma}, whereas IP-10 was expressed in both an IFN-{gamma}-dependent and an IFN-{gamma}-independent fashion. Antibody-mediated neutralization of IP-10 resulted in reduced bacterial clearance and decreased survival, whereas bacterial clearance was unaltered in mice treated with anti-MIG antibody. Impaired bacterial clearance in anti-IP-10 antibody-treated mice was associated with significant reductions in the number and/or activational status of NK and NK-T cells, CD4+ T cells, and {gamma}{delta} T cells, as well as a reduction in the expression of IFN-{gamma}. Conversely, the transient transgenic expression of murine IP-10 using adenovirus-mediated gene transfer resulted in improved bacterial clearance when IP-10 adenovirus was given concomitant with intrapulmonary bacterial challenge. These results indicate that IP-10 is an important component of innate immunity against extracellular bacterial pathogens of the lung and may represent a candidate molecule for immunotherapy in the setting of severe respiratory tract infection.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, 1150 W. Medical Center Drive, Ann Arbor, MI 48109. Phone: (734) 764-4554. Fax: (734) 764-4556. E-mail: tstandif{at}umich.edu.

Editor: J. N. Weiser

Infection and Immunity, December 2005, p. 8226-8236, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8226-8236.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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