Antiviral, Anticellular and Enzyme-inducing Activities of Interferons in RD-114 Cells

Sen, Ganes C.; Herz, Ruth; Rubin, Berish Y.

doi:10.1099/0022-1317-64-10-2213

Cited by 13 publications

(9 citation statements)

References 29 publications

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“…This included the observation that 2-5(A) accumulates in IFN-treated EMCV-infected cells (14), that RNase L is activated in such cells (37), that the inhibition can be partially reversed by analogs of 2-5(A) (36), and that IFN treatment protects RNase L from inactivation by EMCV infection (4). Moreover, in many cell lines, including NIH MOL, RD-114, and NIH 3T3, in which the pathway involving RNase L is defective, EMCV replication is not sensitive to IFN (8, 25,29,32,33).…”

Section: Discussionmentioning

confidence: 99%

“…At present, the only known function of the products of 2-5(A) synthetase [i.e., 2-5(A)] is the activation of latent RNase L, the second enzyme of the 2-5(A) synthetase-RNase L pathway (21). There are data indicating that one or both of the enzymes of this pathway are defective in various IFN-treated cells in which EMCV replication in not impaired (8,13,29,32,33). Moreover, it has been shown that the replicative-intermediate form of EMCV RNA can activate 2-5(A) synthetase (24), that 2-5(A) is accumulated in some IFN-treated, EMCV-infected cells (14), and that rRNA cleavage (thought to be catalyzed by activated RNase L) occurs in some IFN-treated EMCV-infected cells (37).…”

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confidence: 99%

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Studies on the role of the 2'-5'-oligoadenylate synthetase-RNase L pathway in beta interferon-mediated inhibition of encephalomyocarditis virus replication

Kumar

Choubey

Lengyel

et al. 1988

J Virol

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Interferons inhibit the replication of vesicular stomatitis virus (VSV), but not of encephalomyocarditis virus (EMCV), in mouse JLSV-11 cells. We report the isolation of clonal derivatives from this cell line in which the replication of both viruses is impaired by interferons. These clones were selected from the parental line by virtue of their rescue by interferon treatment from the cytopathic effects of EMCV infection. In one such clone, RK8, the replication of VSV and EMCV and the production of resident murine leukemia virus were inhibited by interferon. On the other hand, in clone RK6, which was isolated without any selection, the replication of VSV, but not of EMCV, was impaired by interferons. The levels of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity were similarly elevated upon interferon treatment in the two clones. However, the level of RNase L, as determined by binding and cross-linking of a radiolabeled 2'-5'-oligoadenylate derivative, was much lower in RK6 cells than in RK8 cells. In accord with this observation, the introduction of 2'-5'oligoadenylates into cells inhibited protein synthesis much less strongly in RK6 cells than in RK8 cells. These results are consistent with the notion that the 2'-5'-oligoadenylate-dependent RNase L may be a mediator of the inhibition of EMCV replication by interferons.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Studies on the role of the 2'-5'-oligoadenylate synthetase-RNase L pathway in beta interferon-mediated inhibition of encephalomyocarditis virus replication

Kumar

Choubey

Lengyel

et al. 1988

J Virol

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“…Pure recombinant IFN-aA (a gift from Sidney Pestka) and pure recombinant IFN--y (a gift from Genentech, Inc.) were used for these studies. RD-114 or HeLa cells were grown in monolayers (11,21). When the cells were subjected to a series of treatments with different agents, cells were washed three times with warm culture medium between two consecutive treatments.…”

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confidence: 99%

Transcriptional analyses of interferon-inducible mRNAs.

Kusari¹,

Sen²

1987

Mol. Cell. Biol.

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Using nuclear runoff transcription assays we demonstrated that alpha interferon-mediated induction of transcription of four mRNAs in HeLa monolayer cells needed ongoing protein synthesis and that such a need could be obviated by pretreating the cells with gamma interferon which, by itself, did not induce transcription of these mRNAs. In another human cell line, RD-114, synthesis of alpha interferon-inducible mRNA 561 did not need ongoing protein synthesis. In this line, however, in which interferon inhibits replication of some viruses but not of others, transcription of two of the six interferon-inducible mRNAs that we examined was not appreciably enhanced by interferon.All actions of interferon (IFN) are thought to be mediated by products of a specific set of genes, the expression of which is induced or at least augmented in IFN-treated cells (13,17). Much of the current research on the mechanism of IFN action is focused on identifying these genes, understanding how IFN enhances their expression, and evaluating the specific contributions of the products of these genes toward various actions of IFN.Involvement of an IFN-induced protein in IFN-a-induced synthesis of mRNAs in HeLa cells. We have reported previously (11) that a putative IFN-inducible protein, protein X, is needed for induction of mRNA 561 in HeLa monolayer cells. Protein X can be induced by both IFN-a and IFN--y although IFN--y by itself cannot induce mRNA 561 in these cells. In the experiments reported here we investigated whether induction of three other mRNAs is regulated similarly and whether the protein X-mediated regulation operates at the level of gene transcription.We used nuclear runoff transcription assays to measure the rate of transcription of various mRNAs. Pure recombinant IFN-aA (a gift from Sidney Pestka) and pure recombinant IFN--y (a gift from Genentech, Inc.) were used for these studies. RD-114 or HeLa cells were grown in monolayers (11,21). When the cells were subjected to a series of treatments with different agents, cells were washed three times with warm culture medium between two consecutive treatments. The cDNA clones used were 561 (1, 11, 12, 18); 2-5(A) synthetase (a gift from Bryan Williams [16]); and 1-8, 6-16, and MT-II (gifts from George Stark and Ian Kerr [7]). The cDNA clones were linearized with an appropriate single-cut enzyme and bound to nitrocellulose filters for nuclear runoff assays, which were carried out as described by Friedman et al. (7), but nuclei prepared by the method of Greenberg and Ziff (9) were used.In the experiments shown in Fig. 1, we measured relative rates of transcription of mRNAs 561, 2',5'-oligoadenylate [2-5(A)] synthetase, 6-16, and 1-8 in nuclei isolated from HeLa cells that were treated with IFN for various lengths of time. Maximum transcription rates for all mRNAs were attained at 3 h after IFN-ot treatment had begun. The rates then declined rapidly, even though the cells were in constant contact with IFN-a. IFN-y treatment did not enhance transcription of mRNA 561 and mRNA 2-5(A) syn...

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“…Interferons (IFNs) have a variety of biological activities, including actions against viruses which use different replication strategies (7,13). We have been using cell lines which are partially responsive to IFNs for studying their mechanisms of action (1,3,6,14,15). Replication of some viruses but not of others is inhibited by IFNs in these cell lines.…”

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confidence: 99%

“…Neither IFN has a strong anticellular effect on these cells. The double-stranded RNAdependent enzymes 2',5'-oligoadenylate [2-5(A)] synthetase and protein kinase are induced poorly by IFNs in these lines (15). We recently compared the induction patterns of seven IFN-inducible mRNAs in RD-114 and HeLa cells.…”

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confidence: 99%

Clonal derivatives of the RD-114 cell line differ in their antiviral and gene-inducing responses to interferons

Kumar¹,

Tiwari²,

Kusari³

et al. 1987

J Virol

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The human rhabdomyosarcoma cell line RD-1 14 is partially responsive to interferons (IFNs). In these cells, alpha interferon (IFN-a) or gamma interferon (IFN-y) inhibits the replication of some viruses but not of others.Similarly, some of the IFN-inducible mRNAs are induced poorly, whereas others are induced well. Here we report the isolation of clonal derivatives of this line which display different spectra of responses to IFNs. Among the eight extensively characterized clonal lines, one, CIO, did not respond to IFN-a or IFN--y at all. Retrovirus production by each of the seven other lines was inhibited by both IFN-a and IFN--y. Replication of vesicular stomatitis virus was inhibited strongly by IFN-ot in clone BI but not in others, whereas it was not appreciably affected by IFN-y in any clone. Replication of encephalomyocarditis virus was inhbited strongly by IFN--y in clones Al, A2, A3, B3, and B8 and by IFN-ft in clone A2. Neither IFN inhibited the multiplication of these clones greatly, although their doubling times were slightly increased. Five mRNAs were induced by IFNs to varying degrees in the seven clones. mRNA 2A was most strongly induced by IFN-y in clone A3. mRNA 1-8 was strongly induced by IFN-ct in clone Al and by either IFN in clones A2 and A3. The highest concentrations of 2',5'-oligoadenylate synthetase mRNA, mRNA 561, and mRNA 6-16 were in IFN-a-treated clones Al and A2. These results demonstrated the existence of clonal heterogeneity in IFN responses in a cell line and strengthened the view that IFN treatment of cells generates multiple signals leading to a variety of IFN-induced phenotypes.

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Antiviral, Anticellular and Enzyme-inducing Activities of Interferons in RD-114 Cells

Cited by 13 publications

References 29 publications

Studies on the role of the 2'-5'-oligoadenylate synthetase-RNase L pathway in beta interferon-mediated inhibition of encephalomyocarditis virus replication

Studies on the role of the 2'-5'-oligoadenylate synthetase-RNase L pathway in beta interferon-mediated inhibition of encephalomyocarditis virus replication

Transcriptional analyses of interferon-inducible mRNAs.

Clonal derivatives of the RD-114 cell line differ in their antiviral and gene-inducing responses to interferons

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