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Molecular Medicine Reports Mar 2016Polyinosinic acid:polycytidylic acid, known as poly (I:C), is an analogue of double‑stranded RNA, which exhibits direct antitumor effects against several types of...
Polyinosinic acid:polycytidylic acid, known as poly (I:C), is an analogue of double‑stranded RNA, which exhibits direct antitumor effects against several types of cancer. The present study aimed to evaluate the role of poly (I:C) in the apoptosis of cervical cancer cells. The HeLa human cervical cancer cell line was used in the present study, and cell apoptosis was determined following poly (I:C) transfection. Furthermore, the mRNA levels of interferon (IFN)‑β, the production of reactive oxygen species (ROS), DNA damage, mitochondrial membrane potential (∆Ψm) and the release of cytochrome c, as well as caspase activation, were determined. The effect of IFN‑β on poly (I:C) transfection‑mediated apoptosis was also examined by IFN‑β knockdown. The results showed that poly (I:C) transfection markedly induced HeLa apoptosis, increased the protein levels of pro‑apoptotic B cell lymphoma‑2 (Bcl‑2)‑associated X protein (Bax) and BH3 interacting‑domain death agonist (Bid), and suppressed the protein expression levels of anti‑apoptotic Bcl‑2 and Survivin. However, poly (I:C) transfection increased the mRNA levels of IFN‑β, induced ROS production and increased the levels of phosphorylated γH2A.X, an indicator of DNA damage. In addition, poly (I:C) transfection decreased ∆Ψm, triggered the release of cytochrome c from the mitochondria to the cytosol, and induced caspase‑9 and ‑3 activation. IFN‑β knockdown decreased the poly (I:C)‑induced production of ROS and DNA damage, restored ∆Ψm and cytochrome c release, and suppressed caspase‑9 and ‑3 activation, thereby suppressing poly (I:C)‑mediated apoptosis in the HeLa cells. Together, the results of the present study demonstrated that poly (I:C) transfection induced IFN‑β, contributing to ROS production, DNA damage, and caspase‑9 and ‑3 activation in the HeLa cervical cancer cell line, leading to mitochondrial‑mediated apoptosis.
Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 9; DNA Damage; Female; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria; Poly I-C; Reactive Oxygen Species; Transfection; Uterine Cervical Neoplasms
PubMed: 26848042
DOI: 10.3892/mmr.2016.4848 -
Brain, Behavior, and Immunity Oct 2020Many psychiatric illnesses have a multifactorial etiology involving genetic and environmental risk factors that trigger persistent neurodevelopmental impairments....
Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat 'dual-hit' model for neurodevelopmental disorders.
Many psychiatric illnesses have a multifactorial etiology involving genetic and environmental risk factors that trigger persistent neurodevelopmental impairments. Several risk factors have been individually replicated in rodents, to understand disease mechanisms and evaluate novel treatments, particularly for poorly-managed negative and cognitive symptoms. However, the complex interplay between various factors remains unclear. Rodent dual-hit neurodevelopmental models offer vital opportunities to examine this and explore new strategies for early therapeutic intervention. This study combined gestational administration of polyinosinic:polycytidylic acid (poly(I:C); PIC, to mimic viral infection during pregnancy) with post-weaning isolation of resulting offspring (to mirror adolescent social adversity). After in vitro and in vivo studies required for laboratory-specific PIC characterization and optimization, we administered 10 mg/kg i.p. PIC potassium salt to time-mated Lister hooded dams on gestational day 15. This induced transient hypothermia, sickness behavior and weight loss in the dams, and led to locomotor hyperactivity, elevated striatal cytokine levels, and increased frontal cortical JNK phosphorylation in the offspring at adulthood. Remarkably, instead of exacerbating the well-characterized isolation syndrome, gestational PIC exposure actually protected against a spectrum of isolation-induced behavioral and brain regional changes. Thus isolation reared rats exhibited locomotor hyperactivity, impaired associative memory and reversal learning, elevated hippocampal and frontal cortical cytokine levels, and increased mammalian target of rapamycin (mTOR) activation in the frontal cortex - which were not evident in isolates previously exposed to gestational PIC. Brains from adolescent littermates suggest little contribution of cytokines, mTOR or JNK to early development of the isolation syndrome, or resilience conferred by PIC. But notably hippocampal oxytocin, which can protect against stress, was higher in adolescent PIC-exposed isolates so might contribute to a more favorable outcome. These findings have implications for identifying individuals at risk for disorders like schizophrenia who may benefit from early therapeutic intervention, and justify preclinical assessment of whether adolescent oxytocin manipulations can modulate disease onset or progression.
Topics: Animals; Behavior, Animal; Cytokines; Disease Models, Animal; Female; Neurodevelopmental Disorders; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Social Isolation; TOR Serine-Threonine Kinases
PubMed: 32485291
DOI: 10.1016/j.bbi.2020.05.076 -
Poly(I:C)-Mediated Death of Human Prostate Cancer Cell Lines Is Induced by Interleukin-27 Treatment.Journal of Interferon & Cytokine... Aug 2019Interleukin (IL)-27 is a promising anti-cancer cytokine with therapeutic potential. Exhibiting overlapping properties with type I and II interferons (IFNs), IL-27...
Interleukin (IL)-27 is a promising anti-cancer cytokine with therapeutic potential. Exhibiting overlapping properties with type I and II interferons (IFNs), IL-27 impacts cancer cell viability and immune cell activity. Known to modulate toll-like receptor (TLR) expression, we investigated whether IL-27 affected TLR-mediated death in cancer cells. Using DU145 and PC3 cell lines as models of prostate cancer, we investigated whether IL-27 and IFN-γ affect TLR3-mediated cell death. Our results demonstrate that when IL-27 or IFN-γ is added with polyinosinic-polycytidylic acid [poly(I:C)], type I IFN (IFN-I) expression increases concurrently with cell death. IL-27 and IFN-γ enhanced TLR3 expression, suggesting a mechanism for sensitization to cell death. Further, PC3 cells were more sensitive to IL-27/poly(I:C)-induced cell death compared with DU145 cells. This correlated with higher production of IFN-β and inducible protein-10 versus IL-6 in response to treatment of PC3 cells compared with DU145. Taken together, this study demonstrates a potential role for IL-27 in the treatment of prostate cancer.
Topics: Antineoplastic Agents; Cell Death; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Interleukin-27; Male; PC-3 Cells; Poly I-C; Prostatic Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 31009295
DOI: 10.1089/jir.2018.0166 -
Immunologic Research Aug 2021Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer... (Comparative Study)
Comparative Study Review
Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer regression. These agonists undeniably have some shared characteristics such as mimicking dsRNA but pathways through which they exhibit antitumor properties are relatively diverse. In this review, three widely studied agonists RGC100, ARNAX, and poly-IC are discussed along with their structural and physiochemical differences including the signaling cascades through which they exert their actions. Comparison has been made to identify the finest agonist with maximum effectivity and the least side effect profile.
Topics: Adjuvants, Immunologic; Animals; Humans; Poly I-C; RNA; Toll-Like Receptor 3
PubMed: 34145551
DOI: 10.1007/s12026-021-09203-6 -
International Journal of Pharmaceutics Aug 2018In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated...
In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated intradermal vaccination in mice. The following liposomal formulations were studied: DT loaded liposomes, a mixture of free DT and poly(I:C)-loaded liposomes, a mixture of DT-loaded liposomes and free poly(I:C), and liposomal formulations with DT and poly(I:C) either individually or co-encapsulated in the liposomes. Reference groups were DT solution adjuvanted with or without poly(I:C) (DT/poly(I:C)). The liposomal formulations were characterized in terms of particle size, zeta potential, loading and release of DT and poly(I:C). After intradermal injection of BALB/c mice with the formulations through a hollow microneedle, the immunogenicity was assessed by DT-specific ELISAs. All formulations induced similar total IgG and IgG1 titers. However, all the liposomal groups containing both DT and poly(I:C) showed enhanced IgG2a titers compared to DT/poly(I:C) solution, indicating that the immune response was skewed towards a Th1 direction. This enhancement was similar for all liposomal groups that contain both DT and poly(I:C) in the formulations. Our results reveal that a mixture of DT encapsulated liposomes and poly(I:C) encapsulated liposomes have a similar effect on the antibody responses as DT and poly(I:C) co-encapsulated liposomes. These findings may have implications for future design of liposomal vaccine delivery systems.
Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Cations; Diphtheria Toxoid; Drug Delivery Systems; Drug Liberation; Enzyme-Linked Immunosorbent Assay; Female; Immunoglobulin G; Injections, Intradermal; Liposomes; Mice; Mice, Inbred BALB C; Needles; Particle Size; Poly I-C; Vaccination
PubMed: 29870743
DOI: 10.1016/j.ijpharm.2018.06.001 -
CNS Neuroscience & Therapeutics Aug 2022Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.
METHODS
We evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.
RESULTS
Poly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre- and post-conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor-κB (NF-κB) [SMD = -1.78; CIs (-2.67, -0.88); p = 0.0)], and tumor necrosis factor alpha (TNF-α) [SMD = -16.83; CIs (-22.63, -11.02); p = 0.00].
CONCLUSION
We showed that poly I:C is neuroprotective and acts via the TLR3/NF-κB/TNF-α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.
Topics: Animals; Brain Infarction; Brain Injuries; Brain Ischemia; Cerebral Infarction; NF-kappa B; Neuroprotective Agents; Poly I-C; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha
PubMed: 35510663
DOI: 10.1111/cns.13851 -
Scientific Reports Feb 2023A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since...
A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since social and communicative deficits are included in the first diagnostic criterion of ASD, we aimed to characterize socio-communicative behaviors in the MIA model based on prenatal exposure to poly(I:C). Our previous studies demonstrated impaired socio-communicative functioning in poly(I:C)-exposed adolescent rats. Therefore, the current study sought to clarify whether these changes would persist beyond adolescence. For this purpose, we analyzed behavior during the social interaction test and recorded ultrasonic vocalizations (USVs) accompanying interactions between adult poly(I:C) rats. The results demonstrated that the altered pattern of social behavior in poly(I:C) males was accompanied by the changes in acoustic parameters of emitted USVs. Poly(I:C) males also demonstrated an impaired olfactory preference for social stimuli. While poly(I:C) females did not differ from controls in socio-positive behaviors, they displayed aggression during the social encounter and were more reactive to somatosensory stimulation. Furthermore, the locomotor pattern of poly(I:C) animals were characterized by repetitive behaviors. Finally, poly(I:C) reduced parvalbumin and GAD67 expression in the cerebellum. The results showed that prenatal poly(I:C) exposure altered the pattern of socio-communicative behaviors of adult rats in a sex-specific manner.
Topics: Pregnancy; Male; Humans; Female; Rats; Animals; Behavior, Animal; Autism Spectrum Disorder; Disease Models, Animal; Prenatal Exposure Delayed Effects; Social Behavior; Poly I-C
PubMed: 36732579
DOI: 10.1038/s41598-023-28919-z -
Viruses May 2023Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral...
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut × Alb/HBs) the HBsAg. Herein, the responsiveness of TLR3 and RIG-I in primary parenchymal and non-parenchymal liver cells was determined in vitro and in vivo. Cell type-specific and mouse strain-dependent interferon, cytokine and chemokine expression were observed by LEGENDplex™ and validated by quantitative PCR. In vitro, the hepatocytes, liver sinusoidal endothelial cells and Kupffer cells of Tg1.4HBV-s-rec mice showed poly(I:C) susceptibilities similar to the wild-type controls, while in the remaining leucocyte fraction the interferon, cytokine and chemokine induction was reduced. On the contrary, poly(I:C)-injected 1.4TgHBV-s-rec mice showed suppressed interferon, cytokine and chemokine levels in hepatocytes but increased levels in the leucocyte fraction. Thus, we concluded that liver cells of Tg1.4HBV-s-rec mice, which produce HBV particles and release the HBsAg, responded to exogenous TLR3/RIG-I stimuli in vitro but exhibited a tolerogenic environment in vivo.
Topics: Mice; Animals; Hepatitis B virus; Mice, Transgenic; Hepatitis B Surface Antigens; Toll-Like Receptor 3; Endothelial Cells; Hepatocytes; Liver; Interferons; Cytokines; Hepatitis B; Poly I-C
PubMed: 37243287
DOI: 10.3390/v15051203 -
Neuroscience Letters Sep 2023Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen,...
Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen, polyinosinic-polycytidylic acid (poly(I:C)), is used to induce maternal immune activation in animal models of psychiatric disorders. In the mouse poly(I:C) model, the existence of segment filamentous bacteria (SFB) in the maternal intestine has been reported to be important for the induction of ASD-related behavioral alterations as well as atypical cortical development called cortical patches. This study aimed to elucidate the effect of a single poly(I:C) injection during embryonic day (E) 9 to E16 on offspring's behavior in the ensured absence of maternal SFB by vancomycin drinking in C57BL/6N mice. The cortical patches were not found at either injection timings with poly(I:C) or PBS vehicle, tested in male or female offspring at postnatal day 0 or 1. Prepulse inhibition was decreased in male adult offspring most strongly at poly(I:C) injection timings later than E11, whereas a modest but significant decrease was observed in female offspring with an injection during E12 to E15. The decrease in social interaction was observed in female offspring most conspicuously at injection timings later than E11, whereas a significant decrease was observed in male offspring with an injection during E12 to E15. In conclusion, this study indicated that behavioral alterations could be induced without maternal SFB. The effect on behavior was substantially different between males and females.
Topics: Humans; Mice; Adult; Animals; Female; Male; Mice, Inbred C57BL; Poly I-C; Disease Models, Animal; Bacteria; Cytoskeleton
PubMed: 37652351
DOI: 10.1016/j.neulet.2023.137467 -
Journal of Neuroinflammation Sep 2021The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is...
BACKGROUND
The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation.
METHODS
Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice.
RESULTS
We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus.
CONCLUSION
Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.
Topics: Animals; Chemokines; Cytokines; Female; Hippocampus; Male; Mice; Poly I-C; Sex Characteristics
PubMed: 34488804
DOI: 10.1186/s12974-021-02235-7