title: Interferon-inducible protein 10, but not monokine induced by gamma interferon, promotes protective type 1 immunity in murine Klebsiella pneumoniae pneumonia.
abstract: 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 gammadelta 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.
authors.affiliation: Department of Pathology, Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Xianying
authors.initials: X
authors.lastname: Zeng
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007710:Klebsiella Infections / Q000276:immunology* / Q000378:metabolism; D007711:Klebsiella pneumoniae; D007962:Leukocytes / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
chemical_list: D000906:Antibodies; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D012333:RNA, Messenger; D007371:Interferon-gamma