Induction of interleukins IL-6 and IL-8 by siRNA.
The HIV-1 co-receptor CCR5 has been thought a relevant target for small interfering RNA (siRNA)-based therapeutics. However, recent findings suggest that siRNA can stimulate innate cytokine responses in mammals. All siRNA agents tested were able to down-regulate the expression of CCR5, albeit with different efficiency (51-74% down-regulation), block HIV-induced syncytia formation between HIV-1 BaL-infected and uninfected CD4(+) cells or block single-round HIV-1 infection as measured by a luciferase reporter assay (46-83% inhibition). Conversely, siRNA directed against CCR5 did not affect replication of a vesicular stomatitis virus (VSV) pseudotyped virus, suggesting that inhibition of HIV replication was specific to CCR5 down-regulation. However, two of four siRNA tested were able to induce the production of interleukin (IL) IL-6 (sixfold induction) and IL-8 (ninefold induction) but no interferon (IFN)-alpha, IFN-beta, IFN-gamma, tumour necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, IL-1beta, IL-10 or IL-12p70 cytokine induction was noted. In the absence of detectable IFN-alpha, IL-6 or IL-8 may represent markers of non-specific effects triggered by siRNA.
Pauls
E
E
Retrovirology Laboratory irsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.
Senserrich
J
J
Bofill
M
M
Clotet
B
B
Esté
J A
JA
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000628:therapy; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology*; D008969:Molecular Sequence Data; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology; D014779:Virus Replication
D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019713:Receptors, CCR5