IP-10 mediates selective mononuclear cell accumulation and activation in response to intrapulmonary transgenic expression and during adenovirus-induced pulmonary inflammation.
CXC chemokines that lack the glutamine-leucine-arginine (ELR) motif, including interferon (IFN)-inducible protein 10 (IP-10 or CXCL10), have been shown to mediate the generation of type 1 immune responses. In this study, we found that the intrapulmonary transient transgenic expression of murine IP-10 in mice using adenoviral gene transfer resulted in the early accumulation of neutrophils, natural killer (NK) cells, and NK T cells within the lung, followed by the delayed accumulation of CD4+ T cells. Adenovirus-mediated transgenic expression of IP-10 also resulted in selective activation of mononuclear cells, including gamma(delta)-T cells and NK cells, as manifest by CD69 expression or induction of cell-associated IFN-gamma. Importantly, the intratracheal (i.t.) administration of a control human type 5 adenovirus also caused significant accumulation of NK, NK T, and CD4+ T cells, which was maximal at 7 days post vector administration and was associated with the induction of IP-10. Neutralization of endogenous IP-10 in animals receiving control adenovirus resulted in decreases in the numbers of NK, CD4+, and CD8+ T cells. These results indicate that IP-10 can direct the accumulation and activation of neutrophils and selected mononuclear cells to the lung and that adenovirus-induced IP-10 contributes to lung inflammatory cell recruitment/activation observed in response to adenoviral vectors used for gene therapy.
Zeng
Xianying
X
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Moore
Thomas A
TA
Newstead
Michael W
MW
Deng
Jane C
JC
Lukacs
Nicholas W
NW
Standiford
Theodore J
TJ
D000256:Adenoviridae / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis; D007442:Intubation, Intratracheal; D007694:Killer Cells, Natural / Q000378:metabolism; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D011024:Pneumonia, Viral / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007371:Interferon-gamma; D037181:Lectins, C-Type; D000099192:CD69 Antigens