Intrapulmonary expression of macrophage inflammatory protein 1alpha (CCL3) induces neutrophil and NK cell accumulation and stimulates innate immunity in murine bacterial pneumonia.
Macrophage inflammatory protein 1alpha (MIP-1alpha) (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-1alpha cDNA (AdMIP-1alpha) was constructed to determine the effect of transient intrapulmonary expression of MIP-1alpha on leukocyte recruitment, activation, and bacterial clearance in a murine model of Klebsiella pneumoniae pneumonia. The intratracheal administration of AdMIP-1alpha resulted in both time- and dose-dependent expression of MIP-1alpha mRNA and protein within the lung. Importantly, the intrapulmonary overexpression of MIP-1alpha 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-1alpha 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-1alpha 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.
Zeng
Xianying
X
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA.
Moore
Thomas A
TA
Newstead
Michael W
MW
Hernandez-Alcoceba
Ruben
R
Tsai
Wan C
WC
Standiford
Theodore J
TJ
D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005260:Female; D015316:Genetic Therapy; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae; D008168:Lung / Q000378:metabolism*; D008213:Lymphocyte Activation; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma