Protective roles of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in dengue virus infection of human lung epithelial cells.
Interferons (IFNs) are critical cytokines that regulate immune response against virus infections. Dengue virus (DV) infections are a major public health concern worldwide, and especially in Asia. In the present study, we investigated the effects and mechanisms of action of IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) in human lung epithelial cells. The results demonstrated that DV infection induced expression of several IFITs, including IFIT1, IFIT2, IFIT3, and IFIT5 in A549 cells. Induction of IFIT3 by DV infection was also observed in human dendritic cells. In a knockdown study, we showed that a signal transducer and activator of transcription 2 (STAT2), but not STAT1 or STAT3, regulated DV-induced IFIT3 production. By using several different methods to evaluate cell death, we demonstrated that knockdown of IFIT3 led to cellular apoptosis. Furthermore, knockdown of IFIT3 induced the expression of several apoptotic regulators such as caspase 3, caspase 8, caspase 9, and Bcl-2-associated X protein (BAX). Such apoptotic effects and mechanisms were synergistically enhanced after DV infection. Moreover, under conditions of IFIT3 deficiency, viral production increased, suggesting an anti-viral effect of IFIT3. Interestingly, DV could suppress IFN-α-induced but not IFN-γ-induced IFIT3 expression, a phenomenon similar to the regulation of STATs by DV. In conclusion, this study revealed some mechanisms of IFIT3 induction, and also demonstrated the protective roles of IFIT3 following IFN-α production in DV infection of human lung epithelial cells.
Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Yu-Lin
YL
Hsu
Shao-Fu
SF
Shi
Wan-Lin
WL
Wu
Ling-Jun
LJ
Ho
Jenn-Haung
JH
Lai
D001483:Base Sequence; D020169:Caspases / Q000096:biosynthesis; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D003716:Dengue Virus / Q000502:physiology*; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D055785:Gene Knockdown Techniques; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D034741:RNA, Small Interfering / Q000235:genetics; D050795:STAT2 Transcription Factor / Q000378:metabolism; D014779:Virus Replication
C116468:IFIT3 protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D050795:STAT2 Transcription Factor; D020169:Caspases