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Query: UNIPROT:P06889 (Mol)
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We investigated the binding of 125I-labeled beta interferon (IFN-beta Ser17), a nonglycosylated recombinant human fibroblast interferon in which cysteine at position 17 is replaced by serine by site-specific mutagenesis. An optimized chloramine T radiolabeling method produced a highly labeled, fully active 125I-IFN suitable for these studies. Unlike the case with the chloramine T method, incorporation of a single mole of Bolton-Hunter reagent into a mole of IFN-beta Ser17 led to nearly complete loss of biological activity. 125I-IFN-beta Ser17, prepared by the chloramine T method, bound specifically to human lymphoblastoid cells (Daudi) with a dissociation constant of 0.24 nM. The number of binding sites per cell was 4,000. In competition assays, unlabeled beta interferons (native, recombinant IFN-beta Cys17, and various preparations of IFN-beta Ser17) equally displaced labeled IFN-beta Ser17 on Daudi cells. Recombinant IFN-alpha-1 displaced 125I-IFN-beta binding to Daudi cells less efficiently than did unlabeled native or recombinant beta interferon. However, at the concentrations tested, native gamma interferon showed no competition with 125I-IFN. Our results indicate that IFN-beta Ser17 and native IFN-beta posses similar binding properties.
Mol Cell Biol 1984 Dec
PMID:Binding of 125I-labeled recombinant beta interferon (IFN-beta Ser17) to human cells. 644 89

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.
Mol Cell Biol 1994 Feb
PMID:A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. 750 5

Interstitial deletions of the short arm of chromosome 9 are associated with glioma, acute lymphoblastic leukemia, melanoma, mesothelioma, lung cancer, and bladder cancer. The distal breakpoints of the deletions (in relation to the centromere) in 14 glioma and leukemia cell lines have been mapped within the 400 kb IFN gene cluster located at band 9p21. To obtain information about the mechanism of these deletions, we have isolated and analyzed the nucleotide sequences at the breakpoint junctions in two glioma-derived cell lines. The A1235 cell line has a complex rearrangement of chromosome 9, including a deletion and an inversion that results in two breakpoint junctions. Both breakpoints of the distal inversion junction occurred within AT-rich regions. In the A172 cell line, a tandem heptamer repeat was found on either side of the deletion breakpoint junction. The distal breakpoint occurred 5' of IFNA2; the 256 bp sequenced from the proximal side of the breakpoint revealed 95% homology to long interspersed nuclear elements. One- and two-base-pair overlaps were observed at these junctions. The possible role of sequence overlaps, and repetitive sequences, in the rearrangement is discussed.
Mol Cell Biol 1994 Nov
PMID:Breakpoint junctions of chromosome 9p deletions in two human glioma cell lines. 752 63

There now appears to be evidence to support the view that the type I IFNs are naturally produced negative regulators of growth that also modify cell differentiation. Consistent with this, it appears that the ability to produce and respond to IFN is suppressed in early embryonic development when cell proliferation and differentiation are essential. In the later stages of fetal development, IFN production is de-repressed, and cells show increased sensitivity to IFN, which may be important in regulating cell proliferation and/or differentiation processes or the interaction between fetal and maternal tissues. Interestingly, the IFN system can also be suppressed in disease states such as the development of tumours or in the establishment of a (chronic) viral infection. Therefore, understanding the developmental regulation of the IFN system may be important to understanding and controlling the IFN system in disease. More extensive studies of the developmental stage and tissue-specific expression of type I IFNs and their receptors are necessary, as well as more direct in vivo experiments to further elucidate the role of the IFN system in reproduction and development.
Mol Reprod Dev 1994 Oct
PMID:Role of interferons in the regulation of cell proliferation, differentiation, and development. 753 16

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
Mol Cell Biol 1995 Apr
PMID:Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. 753 79

We have tested the murine macrophagic cell line RAW 264.7 for its ability to undergo activation after exposure to silica particles in vitro. When exposed to silica under controlled conditions (each cell having access to about 10 silica particles), RAW 264.7 cells were able to phagocytose the particles. Concomitantly, there was a significant increase in tumor necrosis factor alpha (TNF alpha) mRNA accumulation and TNF alpha secretion. The level of TNF alpha production by RAW 264.7 cells increased up to 5-fold 48 h after phagocytosis of silica particles with very low cell toxicity. The phagocytic stimulus did not induce nitric oxide production. When cells were exposed to a higher number of silica particles, cell activation was attained at shorter times but a substantial number of cells were damaged at 48 h. Interferon gamma (IFN gamma) alone induced an increased production of TNF alpha in RAW 264.7 cells, not further augmented by a subsequent exposure to silica of the IFN gamma-treated cells. Other macrophage-like cell lines as well as primary peritoneal macrophages were able to phagocytose silica particles but showed different abilities to produce and secrete TNF alpha once phagocytosis took place. Therefore, RAW 264.7 cells were chosen as a model for in vitro studies of the long-term response of macrophages to silica.
Am J Respir Cell Mol Biol 1995 Nov
PMID:Activation of murine macrophages by silica particles in vitro is a process independent of silica-induced cell death. 757 90

Alveolar macrophages (AM) are crucial to initiating and maintaining local immune responses. The increased susceptibility to pulmonary infections in lung allograft recipients may be due to impaired AM function resulting in diminished cellular and humoral immunity. We have previously reported that control AM were potent stimulators of IgG production from allogeneic peripheral blood mononuclear cells (PBM) in a manner that was dependent on gamma-interferon (gamma IFN). The ability of allograft AM to induce IgG production is unknown. The purpose of the current study was to compare the ability of allograft and control AM to induce IgG production from allogeneic PBM. In contrast to control AM which induced a dose-dependent stimulation of IgG production from allogeneic PBM, allograft AM were highly suppressive of IgG production. The inhibition was not due to a lack of allograft AM stimulation of gamma IFN production from responding lymphocytes. Supernatants from allograft AM were highly suppressive of control AM-induced IgG production. Allograft AM produced greater quantities of interleukin (IL-10) than control AM while transforming growth factor-beta (TGF-beta) production from these cells was comparable. Blocking antibodies to IL-10 and TGF-beta reversed the inhibition of IgG production to 63% and 60% of control, respectively. In addition, the production of interleukin 6 (IL-6), a macrophage-derived cytokine crucial to the stimulation of IgG synthesis, was deficient in the allograft AM. Addition of IL-6 to allograft AM and allogeneic PBM co-cultures restored IgG synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Nov
PMID:Effect of human lung allograft alveolar macrophages on IgG production: immunoregulatory role of interleukin-10, transforming growth factor-beta, and interleukin-6. 757 99

Cyclic nucleotide phosphodiesterase (PDE) enzymes may participate in regulation of the inflammatory response through their effects on second messengers. In the present study, we have investigated the role of nonselective and isozyme selective PDE inhibitors in altering the antigen-driven cytokine gene expression of peripheral blood mononuclear cells (PBMCs) from atopic individuals. Ragweed and tetanus toxoid were used as model antigens. The nonselective PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the selective PDE4 inhibitor, rolipram, markedly suppressed interleukin-5 (IL-5) and interferon gamma (IFN gamma) gene expression in both antigen-driven systems. Gene expression for IL-4 was unaffected by these agents in the ragweed-driven system. Message for IL-4 could not be detected in the tetanus toxoid-driven system, despite the use of a quantitative, competitive reverse transcription-polymerase chain reaction (RT-PCR) assay sensitive to less than 10 fg of target template. The PDE3 inhibitor, siguazodan, was ineffective in downregulating gene expression for the proinflammatory cytokines assayed; when used in combination with the PDE4 inhibitor, the PDE3 inhibitor provided no increase in efficacy over that seen with the PDE4 inhibitor alone. Gene expression for the A and B isoforms of the PDE4 in PBMCs was unaffected by antigen stimulation or treatment with the PDE4 inhibitor; however, differences in expression of these two isoforms were apparent when a variety of immune cell lines were studied. These data support the hypothesis that the primary anti-inflammatory target for PDE inhibition in PBMCs is the PDE4. Furthermore, the expression of various isoforms of this enzyme may differ between immune cell types. Finally, PDE4 isoform expression in PBMCs is independent of treatment with an isozyme selective inhibitor.
Am J Respir Cell Mol Biol 1995 Dec
PMID:Effects of nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors on antigen-induced cytokine gene expression in peripheral blood mononuclear cells. 757 7

HIV infection is characterized, at least in part, by the dysregulation of the cytokine network. Both IFN gamma and IFN alpha are occasionally overproduced. These cytokines could participate in the HIV-induced immunosuppression. To enable a HIV-infected organism to promote an immune reaction against the virus, the immune competence should tentatively be restored by counteracting the overproduction of IFN alpha because of its well known antiproliferative properties. For this purpose, IFN alpha was chemically converted into a biologically inactive, but still immunogenic product, which we termed "kinoid", reminiscent of that of bacterial toxins which have been transformed into toxoids for vaccination. The "kinoid" derived from IFN alpha showed to be well tolerated and immunogenic, since its administration to experimental animals and humans should result in no untoward reactions, while eliciting the production of anti-IFN alpha antibodies. Active "kinoid" immunization should permit to counteract the overproduction of the corresponding cytokine when involved in pathogenesis. Another alternative, although less attractive than active anti-kinoid vaccination, is passive immunization by administering anti-kinoid antibodies. Biological antagonists of cytokine, as well as gene therapy should also be taken into consideration.
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:"Kinoids": the basis for anticytokine immunization and their use in HIV infection. 758 Aug 27

A randomized, placebo-controlled trial was designed to evaluate safety and immunogenicity of an anti-cytokine vaccine in high risk HIV-positive patients. This strategy was aimed to modulate the impaired cytokine regulation in AIDS. Twelve asymptomatic patients on antiretroviral therapy for at least 1 year and with CD4 cell counts between 100-300/mm3 were randomized to receive adjuvanted formol-inactivated interferon alpha-2a (IFN alpha) and continue the current antiretroviral treatment, whatever it was, or to receive the adjuvant alone and the current antiretroviral treatment. All patients received 4 i.m. injections monthly, followed by booster injections every 3 months. Clinical status, immunology and virology were monitored. Immune response to vaccination was evaluated in term of antibody detection (ELISA) and serum anti-IFN alpha neutralizing capacity. Only local discomfort and transient fever were reported. All vaccines except one showed increased levels of anti-IFN alpha Abs and developed serum IFN alpha neutralizing capacity. Viral load did not increase in vaccinees while it remained unchanged or even increased in placebo-treated patients. None of them showed HIV-related symptoms and all had their CD4 cell counts stabilized over 18 months, whereas 2 placebo-treated patients developed full-blow AIDS. In conclusion, anti-IFN alpha vaccine was safe and immunogenic. Stable clinical and immunological status over 18 months was observed in vaccinees coupled to increased serum IFN alpha neutralizing capacity.
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:Anti-alpha interferon immunization: safety and immunogenicity in asymptomatic HIV positive patients at high risk of disease progression. 758 Aug 31


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