Journal of Interferon Research

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ISSN : 0197-8357
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Susan B. Klein, Agnes Yeivin, Gerald Becker, Milton W. Taylor
Journal of Interferon Research, Volume 14, pp 333-341;

Genetic analyses of mutants have yielded valuable information about p91-associated interferon signal transduction. It was thus discovered that p91 is an essential protein for the induction of both type I and type II interferons. We previously reported the development of ME180 mutants resistant to interferon-gamma because of a signaling defect resulting in the loss of IDO induction. IDO does not respond to type I interferon despite an ISRE-like sequence upstream of the coding region. However, the IDO mutants were found to be cross-resistant to the growth-inhibitory effects of type I interferon. We therefore examined the effects of both types of interferon on interferon-stimulated gene mRNA accumulation and examined alterations in cellular protein introduced by the mutation. The induction of the p91-responsive gene 6-16 was not altered in either of the mutants, and the early-induced gene IRF1 exhibited differences only in the kinetics of mRNA accumulation. The later induced gene, p68, also exhibited different kinetics, possibly reflecting the changes in IRF1. Immunoprecipitated p91 exhibited normal, interferon-induced phosphorylation in both mutants. Two-dimensional gel electrophoresis revealed that the mutant cells contained 20 peptides with altered biochemistry. These results suggest that IDO induction is controlled by a distinct set of proteins not directly correlated with p91 activation.
Chaoqun Wu, , Sudip Bandyopadhyay, Ganes C Sen, Thomas A Hamilton
Journal of Interferon Research, Volume 14, pp 357-363;

To understand the mechanisms involved in dsRNA-induced gene expression, we analyzed the poly(I/C)-induced transcription of the IFN-inducible chemokine gene IP-10 using the GRE cell line in which type I IFN genes have been deleted. Accumulation of IP-10 mRNA in GRE cells was more strongly stimulated by treatment with dsRNA than by IFN-alpha or IFN-gamma and was independent of protein synthesis. This same pattern of response was produced when GRE cells were transiently transfected with a plasmid containing 243 bases of sequence from the promoter of the murine IP-10 gene linked to the chloramphenicol acetyltransferase reporter gene. Deletion- and site-specific mutagenesis of the 243 base pair fragment indicated that an ISRE located between residues -204 and -228 was a primary target site for the action of dsRNA on this promoter. This was confirmed by results showing that two copies of this ISRE tandemly arrayed in front of the thymidine kinase promoter were able to mediate reporter gene transcription in dsRNA-stimulated cells. At least one of the two NF kappa B binding sites present in the 243 base pair IP-10 promoter is also necessary for response to dsRNA; mutation of both sites eliminates promoter activity. Thus the ISRE and one NF kappa B site cooperate to produce transcriptional response to dsRNA.
, Gurmel S. Sidhu, Anoop K. Singh, Sudha S. Sivaram, Paul R. Kinchington, John Hay, Robert M. Friedman
Journal of Interferon Research, Volume 14, pp 319-324;

We have investigated the mechanism(s) of interferon (IFN)-induced inhibition of assembly steps of herpes simplex virus (HSV-1) in mouse LB cells. Data showed that physiological doses of mouse IFN-beta (10-100 IU/ml) significantly inhibited the infectivity (5- to 100-fold) of HSV-1; however, viral protein synthesis was marginally inhibited (2- to 5-fold). Immunofluorescence studies showed that most of the HSV-1gD glycoprotein accumulated intracellularly in IFN-treated LB and LMtk- cells transfected with gD cDNA, as compared to untreated controls, where most of the gD was localized on the plasma membrane. Double-immunofluorescence studies demonstrated that rhodamine-labeled wheat germ agglutinin (WGA) was co-localized with gD protein, suggesting the block was in the transport from the trans-Golgi to the plasma membrane. IFN treatment of LB and LMtk- cells raised the intracellular pH as measured by DAMP distribution and SNARF-1 using laser spectroscopy; this could play an important role in the inhibition of transport of HSV-1gD.
A.M. Liberati, M.A. Horisberger, P. Garofani, V. De Angelis, A. Ferrajoli, F. Di Clemente, P. Caricchi, D. Adiuto, L. Fedeli, B. Palumbo
Journal of Interferon Research, Volume 14, pp 349-355;

Serum neopterin (Np), beta 2-microglobulin (beta 2-M), and 2',5'-adenylate (2',5'A) levels and intracellular 2',5'A and human Mx (Hu-Mx) protein synthesis were measured in 20-24 chronic myeloid leukemia patients before and during 1 year of IFN-alpha treatment and in a further 8-9 patients before and at the end of the first and second treatment weeks only. Univariate analysis showed that IFN-alpha increased Np and 2',5'A serum levels and intracellular concentrations of 2',5'A and Hu-Mx significantly from the end of the first week to month 12 of therapy. The biologic marker profiles were similar in cytogenetic responders and nonresponders, as well as in patients treated with IFN-alpha early (< 12 months from diagnosis) or late (after > 12 months standard chemotherapy). Further, there were no differences in the short-term (first 14 days) or long-term (during 12 month therapy) induction of the biologic markers irrespective of whether IFN-alpha 2a or IFN-alpha 2b was given. Because multivariate analysis revealed no significant interactions between cytogenetic response, time to treatment, and type of IFN-alpha used, increments in intracellular 2',5'A and Hu-Mx protein were similar at all study times for all factor combinations tested. Np levels varied significantly only during the first 14 therapy days; changes in serum 2',5'A were never statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
, Jennifer Haslam, Linda Kessler, H. Martin Seidel, Robert B. Stein, Jon Rosen
Journal of Interferon Research, Volume 14, pp 365-373;

Induction of gene expression by interferon-gamma involves the activation of a latent cytoplasmic transcription factor, p91, by phosphorylation on a single tyrosyl residue. This phosphorylation triggers dimerization, nuclear translocation, and the binding of p91 to interferon-gamma response elements present in the promoters of induced genes. Phosphorylation of p91 requires the activation of two tyrosine kinases, JAK1 and JAK2, that themselves become phosphorylated on tyrosyl residues shortly after interferon-gamma binds to its receptor. The importance of tyrosine phosphorylation in this pathway prompted us to investigate the role of protein tyrosine phosphatases in the regulation of the pathway. We find that in the absence of interferon-gamma, treatment of cells with an inhibitor of tyrosine phosphatases causes a rapid and potent activation of the components of the interferon-gamma signal transduction pathway and induces an interferon-gamma-responsive gene. This suggests that tyrosine phosphatases act both to repress the interferon-gamma signal transduction pathway in the absence of interferon-gamma and to downregulate the pathway after interferon-gamma induction.
Mario DiPaola, Teresa Smith, Kathy Ferencz-Biro, Mei-June Liao, Douglas Testa
Journal of Interferon Research, Volume 14, pp 325-332;

Peripheral blood leukocytes, isolated from the buffy coats of greater than 10,700 normal healthy donors, were induced with Sendai virus to produce biologically active interferon a (IFN-α). The IFN-α was purified to near homogeneity by immunoaffinity chromatography, followed by size-exclusion chromatography. The resultant product, IFN-αn3, is reproducibly ≥98% pure (to be reported elsewhere). The different IFN-α proteins in IFN-αn3 were separated by reverse-phase high performance liquid chromatography (RP-HPLC) and the identity of the IFN-α2 isolated by HPLC was determined by amino-terminal sequencing. IFN-α2 was found to migrate as two closely eluting peaks on RP-HPLC, and they have been designated as peaks 1.1 and 1.2. Distinction among the three possible variants of IFN-α2, i.e., IFN-α2a, IFN-α2b,, and IFN-α2c, was determined by amino-terminal sequencing of the first 35 amino acids in peaks 1.1 and 1.2. Protein sequence data showed that the discriminating amino acids found at positions 23 and 34 are Arg and His, respectively. The presence of Arg and not Lys at amino acid position 23 and His at amino acid position 34 argues that IFN-α2b, is the major component in the Sendai virus-induced leukocyte IFN-α2 and that IFN-α2a is not present. These findings were verified by subjecting RP-HPLC peaks 1.1 and 1.2 to CNBr cleavage, followed by separation of the fragments by RP-HPLC and sequencing. The sequence of CNBr fragment 3 from both peaks, consisting of a peptide from amino acid positions 22–59, revealed Arg at amino acid position 23 and predominantly His at position 34. Tryptic digestion of isolated CNBr fragment 3, followed by HPLC separation and sequencing, demonstrated the presence of a tryptic peptide with sequence DRHDF..., corresponding to IFN-α2b. Another peptide with sequence DFGF..., which corresponds to IFN-α2c., was also found to be present in a very low concentration. From these data we conclude that the majority of IFN-α2 found in IFN-αn3 is IFN-α2b,, with a minor contribution by IFN-α2c, and that IFN-α2a is not present.
Srecko Koren, W. Robert Fleischmann
Journal of Interferon Research, Volume 14, pp 343-347;

Interferons α, β, and γ have been shown to exert systemic effects following their oral administration to mice. It was of importance to determine whether oral administration of another biologic response modifier, interleukin-2 (IL-2), could also exert systemic effects in mice. Two systemic effects, peripheral WBC suppression and bone marrow suppression, were evaluated. Oral administration of IL-2 was found to suppress the peripheral WBC count in a dose-dependent manner. Oral administration of IL-2 was also found to suppress the bone marrow proliferative activity. The levels of suppression of both peripheral WBC and myelopoietic progenitor cell numbers observed with orally administered IL-2 were comparable to those seen with subcutaneously administered IL-2. The results demonstrate that orally administered IL-2 can exert systemic effects. Further, the results raise the possibility that oral administration of IL-2 may have therapeutic potential.
Wei Dai, Huiqi Pan, Oliver Kwok, J.P. Dubey
Journal of Interferon Research, Volume 14, pp 313-317;

Interferon-gamma (IFN-gamma) is known to inhibit the growth of Toxoplasma gondii both in vivo and in vitro. The IFN-gamma induced anti-toxoplasma activity in human cells is strongly correlated with the degradation of the essential amino acid L-tryptophan in vitro. Destruction of L-tryptophan is due to an increased activity of indoleamine 2,3-dioxygenase (IDO), which is transcriptionally activated by IFN-gamma. To determine if indoleamine 2,3-dioxygenase alone is sufficient to block the T. gondii growth, we transfected human fibroblast cells with an IDO cDNA expression plasmid using a metallothionein-inducible promoter. We showed that IDO mRNA and its enzymatic activity are inducible in fibroblast cells transfected with right-orientation IDO cDNA upon addition of CdCl2 to culture medium. The elevated IDO enzyme activity is strongly correlated with an inhibition of T. gondii growth. No IDO mRNA nor enzyme activity is induced by CdCl2 in reverse orientation transfected cells, and no adverse effects were observed on T. gondii growth in cells transfected with the reverse IDO-construct or in control parent cells with or without supplementation of CdCl2. Our observations along with the recent report by Habara-Ohkubo et al. (Infect. Immun. 61, 1810-1813, 1993) suggest that IFN-gamma-induced antitoxoplasma activity is due at least in part to the activation of IDO gene.
S Koren, W R Fleischmann
Published: 1 December 1994
Journal of Interferon Research, Volume 14

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Igor Tamm, Toyoko Kikuchi, David Kreutter, W. Jackson Pledger,
Journal of Interferon Research, Volume 14, pp 265-273;

Interferon-α/β (IFN-α/β) suppresses cell cycle activation by platelet-derived growth factor (PDGF) as well as the induction of the 31-kD (pI) and the 35-kD (pH) proteins in density-arrested BALB/c-3T3 cells.(1,2) We report that elevation of [Ca2+]i by ionomycin induces the synthesis of the 31-kD protein, but not that of the 35-kD protein. Since IFN blocks the PDGF-induced elevation of [Ca2+]i,(3) these results suggest that IFN treatment may suppress pI induction by impairing this PDGF-activated signal transduction pathway. In contrast, because ionomycin did not induce the 35-kD protein, the suppression by IFN of PDGF-induced pII appears to be mediated via a pathway distinct from that operating in the suppression of pI. In BALB/c-3T3 cells, IFN-α/β did not itself affect the turnover or de novo synthesis of inositol phospholipids and the cellular content of diacylglycerol, nor did IFN block the enhancement of these parameters by PDGF.
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