Toxic Properties of a Synthetic Double-stranded RNA: Endotoxin-like Properties of Poly I.Poly C, an Interferon Stimulator

Absher, Marlene; Stinebring, Warren R.

doi:10.1038/223715a0

Cited by 117 publications

(59 citation statements)

References 17 publications

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“…A viral replication product, dsRNA and its analog polyI:C (6, 7), induced acute inflammation, and has been expected to be a promising therapeutic agent against cancer. Although polyI:C exerts life-threatening cytokinemia (8), trials for its clinical use as an adjuvant continued because of its high therapeutic potential (9,10). Pathogen-associated molecular patterns (PAMPs) and host cell factors induced secondary to PAMP-host cell interaction act as a double-edged sword in cancer prognosis and require understanding their multifarious functional properties in the tumor environment.…”

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confidence: 99%

Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

Shime¹,

Matsumoto²,

Oshiumi³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

168

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Smoldering inflammation often increases the risk of progression for malignant tumors and simultaneously matures myeloid dendritic cells (mDCs) for cell-mediated immunity. PolyI:C, a dsRNA analog, is reported to induce inflammation and potent antitumor immune responses via the Toll-like receptor 3/Toll-IL-1 receptor domain-containing adaptor molecule 1 (TICAM-1) and melanoma differentiation-associated protein 5/IFN-β promoter stimulator 1 (IPS-1) pathways in mDCs to drive activation of natural killer cells and cytotoxic T lymphocytes. Here, we found that i.p. or s.c. injection of polyI:C to Lewis lung carcinoma tumor-implant mice resulted in tumor regression by converting tumor-supporting macrophages (Mfs) to tumor suppressors. F4/80− Mfs infiltrating the tumor respond to polyI:C to rapidly produce inflammatory cytokines and thereafter accelerate M1 polarization. TNF-α was increased within 1 h in both tumor and serum upon polyI:C injection into tumorbearing mice, followed by tumor hemorrhagic necrosis and growth suppression. These tumor responses were abolished in TNF-α −/− mice. Furthermore, F4/80 + Mfs in tumors extracted from polyI:Cinjected mice sustained Lewis lung carcinoma cytotoxic activity, and this activity was partly abrogated by anti-TNF-α Ab. Genes for supporting M1 polarization were subsequently up-regulated in the tumor-infiltrating Mfs. These responses were completely abrogated in TICAM-1 −/− mice, and unaffected in myeloid differentiation factor 88 −/− and IPS-1 −/− mice. Thus, the TICAM-1 pathway is not only important to mature mDCs for cross-priming and natural killer cell activation in the induction of tumor immunity, but also critically engaged in tumor suppression by converting tumor-supporting Mfs to those with tumoricidal properties.Toll-like receptor | tumor-associated macrophages | TRIF

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mentioning

confidence: 99%

Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

Shime¹,

Matsumoto²,

Oshiumi³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

168

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“…The effects of repeated injectionsof interferon inducers were explored in mice given two doses of MA/DVE 5 days apart, and mice given (poly rI) * (poly rC) 2 days after endotoxin. Both treatment schedules are known to significantly diminish the interferon response to the second stimulus (6,34,35). Pretreatment of mice with MA/DVE not only reduced the interferon-inducing capacity but also abolished the protective activity of a second dose 5 days later (Table IV).…”

Section: Resultsmentioning

confidence: 99%

The role of interferon in the protective effect of a synthetic double-stranded polyribonucleotide against intranasal vesicular stomatitis virus challenge in mice

Clerco¹,

Nuwer²,

Merigan³

1970

J. Clin. Invest.

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A B S T R A C T Intravenous injection of polyinosinic acid/polycytidylic acid [(poly rI) * (poly rC)] offered significant protection against intranasal challenge of young mice with vesicular stomatitis virus (VSV). Optimal protection was obtained when a single dose was administered 2 hr before virus challenge, but repeated doses were effective when started as late as 3 days after virus challenge. The therapeutic ratio or ratio of maximum tolerated dose to minimum effective dose for a single intravenous injection of (poly rI) *(poly rC) 2 hr before virus inoculation was > 8 mg/kg: 0.004 mg/ kg or > 200. Dose-response curves for interferon production and antiviral protection by (poly rI) -(poly rC) were closely parallel. Equivalent doses of poly rI or poly rC alone did not exert any interferon-inducing capacity or protective effect on intranasal VSV challenge. Several factors, which are known to potentiate or antagonize interferon production, increased or decreased the interferon-inducing capacity and antiviral protection of either (poly rI) * (poly rC) or maleic acid/divinyl ether copolymer (MA/DVE) in parallel. Interferon production and antiviral protection by MA/DVE were enhanced by arginine but abolished by prior treatment with MA/DVE; DEAE-dextran (intraperitoneally), kinetin riboside and isopentenyladenosine, and prior injection of endotoxin reduced both interferon production and antiviral protection by (poly rI) -(poly rC).Treatment with exogenous interferon in amounts which closely mimicked the levels of circulating interferon produced endogenously by an effective dose of (poly rI) * (poly rC) gave protection against intranasal

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“…The lethal effect of poly(I .C) in mice requires doses of about 500 pg per mouse (14) and signs of general toxicity, such as ruffled fur or behavioral change, require doses greater than or equal to 100 ,ug in our strain (Jahiel, unpublished observations From the viewpoint of experimental therapeutics, the present experiments show that inhibition of certain types of post-embryonic cell division should be looked for in investigations of the harmful side effects of the inducers of interferon. On the other hand, the inducers might be capable of limiting excessive or undesirable multiplication of cells, for instance in hyperplastic changes or precancerous cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Inducers of Interferon Inhibit the Mitotic Response of Liver Cells to Partial Hepatectomy

Jahiel

Taylor

Rainford

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

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Partially hepatectomized mice were injected with inducers of interferon, and the mitotic activity of liver cells was measured. The inducers were polyriboinosinic * polyribocytidylic acid, poly(I * C), Newcastle disease virus, and statolon. Each inhibited the mitosis of liver cells. Poly(I-C) was effective in doses as low as 1 ug per mouse. Polyriboinosinic acid, poly(I), had no inhibitory effect. These results extend the spectrum of action of inducers of interferon to inhibition of mitotic division of an aneoplastic, nonaneuploid mammalian cell.The possibility that interferon and its inducers might inhibit the multiplication of mammalian cells has often been considered. Protection against transplantable tumors has been achieved with interferon (1) and its inducers (2), and chemically induced tumorigenesis has been inhibited by poly(I -C) (3). However, mechanisms other than direct inhibition of multiplication of tumor cells, such as enhancement of immune responses or other indirect effects exerted through the host, could have been involved. Studies of the effects of interferon on cell cultures have been complicated by the unavailability of pure preparations of interferon, since the impurities might have growth-inhibitory effects. Initial reports of such studies were conflicting (4), but recent experiments with preparations derived from various sources suggest that interferon may inhibit multiplication of an established mouse tumor cell line (5). Isoproterenol-induced DNA synthesis in salivary-gland epithelium was inhibited by poly(I* C) (6), but it was not stated whether other inducers of interferon were capable of the same effect. It was also not known whether poly(I .C) was effective only against isoproterenol-induced DNA synthesis, or whether it had a more general inhibitory effect on the division of normal cells.We have now studied the effect of several inducers of interferon on the mitotic division of liver cells that is stimulated by partial hepatectomy; we find that division of such cells is inhibited. MATERIALS AND METHODS Hepatectomy7-week-old, female, CF1 mice (Carworth farms), weighing 19-23 g, were anesthetized with-sodium pentobarbital (0.6 mg/mouse) given intraperitoneally, supplemented by inhalation of ether. Ligatures were tied around the left lateral and median lobes of the liver and most of the median lobe and two-thirds of the left lateral lobe were removed and weighed. The total liver weight (determined in other mice of the same age and weight) ranged from 1.1 to 1.7 g. The portion of liver removed usually weighed from 0.6 to 0.85 g. Mice were matched after hepatectomy so that median weights and ranges of weight of excised liver were nearly equal in all groups of the same experiment. Measurement of mitotic activityMice were killed by cervical dislocation. Specimens from the right lateral lobe of the liver were fixed in Carnoy's solution and sections were stained with hematoxylin and eosin. The mitotic nuclei and interphase nuclei of the parenchymal cells were enumerated with the help o...

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Toxic Properties of a Synthetic Double-stranded RNA: Endotoxin-like Properties of Poly I.Poly C, an Interferon Stimulator

Cited by 117 publications

References 17 publications

Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

The role of interferon in the protective effect of a synthetic double-stranded polyribonucleotide against intranasal vesicular stomatitis virus challenge in mice

Inducers of Interferon Inhibit the Mitotic Response of Liver Cells to Partial Hepatectomy

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