Adenoviral expression of suppressor of cytokine signaling-1 reduces adenovirus vector-induced innate immune responses.
Adenovirus (Ad) vectors are among the most commonly used viral vectors in gene therapy clinical trials. However, the application of Ad vectors has been limited to local injection in many cases, because the systemic administration of Ad vectors triggers innate immune responses such as inflammatory cytokine production and tissue damage. To overcome this limitation, it will be necessary to develop safer Ad vectors less likely to induce the innate immune response. In the present study, we demonstrated that a suppressor of cytokine signaling-1 (SOCS1)-expressing Ad vector, Ad-SOCS1, reduces the innate immune response induced by Ad vectors. RAW264.7-SOCS1, a macrophage-like cell line that stably expresses SOCS1, was shown to produce lower levels of inflammatory cytokines after the transduction of Ad vectors. The systemic administration of Ad-SOCS1 into mice elicited the reduced production of inflammatory cytokines, as compared with that elicited by control Ad vectors, i.e., luciferase-expressing Ad vector, Ad-L2. Furthermore, the coadministration of Ad-L2 with Ad-SOCS1 attenuated inflammatory cytokine production and liver toxicity as compared with injection with Ad-L2 alone, and this was achieved without the suppression of luciferase production in various organs. The JAK/STAT pathway was involved in Ad vector-mediated cytokine production, which was impaired by the overexpression of SOCS1. These findings indicate that Ad-SOCS1 could be useful for reducing Ad vector-mediated innate immunity.
Sakurai
Haruna
H
Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
Tashiro
Katsuhisa
K
Kawabata
Kenji
K
Yamaguchi
Tomoko
T
Sakurai
Fuminori
F
Nakagawa
Shinsaku
S
Mizuguchi
Hiroyuki
H
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics*; D007113:Immunity, Innate / Q000276:immunology*; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D016207:Cytokines; D050791:STAT Transcription Factors; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases