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Infection and Immunity, March 2003, p. 1306-1315, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1306-1315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Intrapulmonary Expression of Macrophage Inflammatory Protein 1{alpha} (CCL3) Induces Neutrophil and NK Cell Accumulation and Stimulates Innate Immunity in Murine Bacterial Pneumonia

Xianying Zeng,1 Thomas A. Moore,1 Michael W. Newstead,1 Ruben Hernandez-Alcoceba,2 Wan C. Tsai,3 and Theodore J. Standiford1*

Department of Medicine, Division of Pulmonary and Critical Care Medicine,1 Division of Hematology/Oncology,2 Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan 48109-03603

Received 7 August 2002/ Returned for modification 3 October 2002/ Accepted 29 November 2002

Macrophage inflammatory protein 1{alpha} (MIP-1{alpha}) (CCL3) is an important mediator of leukocyte recruitment and activation in a variety of inflammatory states, including infection. A recombinant human type 5 adenovirus containing the murine MIP-1{alpha} cDNA (AdMIP-1{alpha}) was constructed to determine the effect of transient intrapulmonary expression of MIP-1{alpha} on leukocyte recruitment, activation, and bacterial clearance in a murine model of Klebsiella pneumoniae pneumonia. The intratracheal administration of AdMIP-1{alpha} resulted in both time- and dose-dependent expression of MIP-1{alpha} mRNA and protein within the lung. Importantly, the intrapulmonary overexpression of MIP-1{alpha} resulted in a maximal 35- and 100-fold reduction in lung and blood bacterial burden, respectively, in animals cochallenged with K. pneumoniae, which was associated with a significant increase in neutrophil and activated NK cell accumulation. Furthermore, the transgenic expression of MIP-1{alpha} during bacterial pneumonia resulted in enhanced expression of gamma interferon mRNA, compared to that observed in Klebsiella-challenged animals pretreated with control vector. These findings indicate an important role for MIP-1{alpha} in the recruitment and activation of selected leukocyte populations in vivo and identify this cytokine as a potential immunoadjuvant to be employed in the setting of localized bacterial infection.

* Corresponding author. Mailing address: The University of Michigan Medical Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, 6301 MSRBIII, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0642. Phone: (734) 764-4554. Fax: (734) 764-4556. E-mail: tstandif{at}umich.edu.

Editor: D. L. Burns

Infection and Immunity, March 2003, p. 1306-1315, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1306-1315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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