Expression of human interleukin-1 receptor antagonist in mouse lungs using a recombinant adenovirus: effects on vector-induced inflammation.
Pulmonary inflammation is a major obstacle to using adenovirus-based vectors for gene transfer to the lung. Since the pro-inflammatory cytokine, interleukin-1 (IL-1), is expressed early following adenovirus infection, we hypothesized that inhibition of IL-1 might block the inflammation caused by adenoviral vectors. To inhibit IL-1 activity at the site of infection continuously, we employed a recombinant adenovirus that contained the cDNA for human IL-1 receptor antagonist protein (IL-1ra) designated as Ad.RSVIL-1ra. When Ad.RSVIL-1ra was instilled intratracheally into CBA/J mice, human IL-1ra was recovered in lung tissue and bronchoalveolar lavage fluid for up to 30 days. Human IL-1ra is known to bind to murine IL-1 receptors and inhibit IL-1-mediated responses. To measure pulmonary inflammation, the number of inflammatory cells contained within suspensions of protease-digested lung tissue were counted 6 days after virus administration. Ad.RSVIL-1ra failed to reduce the number of inflammatory cells below that induced by a control vector that lacked an expression cassette (Ad.BgIII). Light microscopy showed that the lung tissue from Ad.RSVIL-1ra and Ad.BgIII-treated mice contained qualitatively similar amounts of inflammatory infiltrate. We conclude that adenovirus-based vectors can be used to induce high levels of IL-1ra expression within the lung, but such expression was unable to prevent adenoviral vector-induced inflammation.
McCoy
R D
RD
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor 48109-0360, USA.
Davidson
B L
BL
Roessler
B J
BJ
Huffnagle
G B
GB
Simon
R H
RH
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D053590:Interleukin 1 Receptor Antagonist Protein; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins