Domains of Interaction between Alpha Interferon and its Receptor Components

Uzé, Gilles; Marco, Stefania Di; Mouchel-Vielh, Emmanuèle; Monneron, D; Bandu, Marie‐Thérèse; Horisberger, Michel A.; Dorques, A; Lutfalla, Georges; Mogensen, K. E.

doi:10.1006/jmbi.1994.1651

Cited by 108 publications

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“…After proteolytic cleavage of the signal peptide, the truncated protein would consist of only 30 aa. As proposed by Uzé et al 30 31 So far, the exact location of the intergenic microsatellite within the IFN region is not known. LD data obtained in this study provide evidence, that the (GT) n repetition is located centromeric, close to the IFNA17 gene.…”

Section: Discussionmentioning

confidence: 97%

The interferon gene cluster: a candidate region for MS predisposition?

et al. 1999

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The clinical benefits of interferon (IFN) ␤ therapy in some multiple sclerosis (MS) patients are still unexplained, raising the question whether polymorphism within the IFNB gene itself would provide an explanation. Screening the IFNB gene by single strand conformation polymorphism (SSCP) analysis and sequencing, a single nucleotide polymorphism was identified. Both alleles were distributed with similar frequencies in MS patients and controls.

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Section: Discussionmentioning

confidence: 97%

The interferon gene cluster: a candidate region for MS predisposition?

et al. 1999

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“…The mutations were introduced into the human IFN-␤ gene carried on plasmid pJC017, a COS cell expression vector (Biogen, Inc. Cambridge, MA), using the transformer site-directed mutagenesis kit from CLONTECH Laboratories, Inc. (Palo Alto, CA). COS 7 cells were transiently transfected, and the supernatants from cultures (3 days posttransfection) were screened for the presence of immunoreactive IFN-␤ and then for biological activity on human HL116 cells, which carry a luciferase reporter under control of an IFN-␣-␤-inducible promoter (33). Quantitation of IFN expression levels was performed by enzyme-linked immunosorbent assay utilizing rabbit polyclonal anti-IFN-␤1a serum to coat plates, biotinylated rabbit polyclonal antibodies as a secondary reagent, followed by streptavidin-coupled horseradish peroxidase (Jackson Immunochemical, West Grove, PA).…”

Section: Methodsmentioning

confidence: 99%

“…This hybrid, in which part of the B helix, the BC loop, and part of the C helix are derived from human IFN-␣1, is labeled P. Construction, expression, purification, and characterization of the P mutants have been described in detail elsewhere (33).…”

Section: Methodsmentioning

confidence: 99%

“…The derivation and construction of the human HL116 cell line, carrying the luciferase gene under control of the IFN-inducible 6 -16 promoter, and its use in the assay of IFNs has been described in detail elsewhere (33). End points were at 50% luciferase induction and assays were repeated to obtain a precision (95%) of approximately Ϯ0.3 log titer.…”

Section: Methodsmentioning

confidence: 99%

“…15 and 32) allows identification of putative domains likely to be involved in receptor interactions. Examination of structural models in regions of mutational hotspots, such as the AB loop, D helix, DE loop (32), and the C helix (33,34), directed us to exposed residues available for receptor binding.…”

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confidence: 99%

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Differences in Activity between α and β Type I Interferons Explored by Mutational Analysis

Runkel¹,

Pfeffer²,

Lewerenz³

et al. 1998

Journal of Biological Chemistry

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Type I interferon (IFN) subtypes ␣ and ␤ share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, ␣ and ␤ IFNs exhibit key differences in several biological properties. For example, IFN-␤, but not IFN-␣, induces the association of tyrosine-phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor-associated, Janus kinase tyk2. To define the structural basis for these functional differences we produced human IFN-␤ with point mutations and compared them to wild-type IFN-␤ in assays that distinguish ␣ and ␤ IFN subtypes. IFN-␤ mutants with charged residues (N86K, N86E, or Y92D) introduced at two positions in the C helix lost the ability to induce the association of tyrosine-phosphorylated receptor chains and had reduced activity on tyk2-deficient cells. The combination of negatively charged residues N86E and Y92D (homologous with IFN-␣8) increased the cross-species activity of the mutant IFN-␤s on bovine cells to a level comparable to that of human IFN-␣s. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtypespecific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-␣ mutations. The effects of these mutations on IFN-␤ activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.The mammalian type I IFNs, 1 produced in response to viral infection and other inducers, are divided into ␣ and ␤ subtypes on the basis of their reactivity with antisera raised against IFNs derived, respectively, from leukocytes and fibroblasts (1). The human IFN-␣s are encoded by a family of at least 15 different genes, while IFN-␤ is the unique member of its subtype (2). Primary sequence comparison between the ␣ and ␤ subtypes reveal an approximately 50% amino acid homology, while the amino acid homologies between the IFN-␣ subtypes are approximately 80% (2, 3), reinforcing the division between IFN-␣ and -␤ subtypes.As the pleiotropic nature of these cytokines became apparent, with both subtypes eliciting a similar range of biological activities (3), differences between ␣ subtypes, and between IFN-␣ and -␤s, in potency and cell type specific activities were noted (4). In particular, IFN-␤ elicits a markedly higher antiproliferation response in some cell types such as (5), embryonal carcinoma, melanoma and melanocytes than do IFN-␣s (6, 7, and references therein). Higher potency of IFN-␤ in treatment of multiple sclerosis and certain cancers has been observed (7).The entire class of type I IFNs elicit their biological activities through engagement of a common cell surface receptor (8 -10). Two chains of the receptor, ifnar1 and ifnar2, both members of the type two cytokine receptor family, have been identified (11-15). Both components are necessary for function and in the absence of either there is neither...

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Effects of interferon alpha on human osteoprogenitor cell growth and differentiation in vitro

et al. 1999

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The specific effects of interferon alpha (IFN␣), on the differentiation pathways of human osteogenic cells are not known. The aim of this study was to investigate possible effects of IFN␣ on osteogenic development by investigating cell differentiation, colony formation (colony forming unit-fibroblastic, CFU-F), cell proliferation, and gene expression, in particular bone morphogenetic protein (BMP) expression, of human bone marrow osteoprogenitor cells. Human bone marrow fibroblasts were cultured with or without the addition of IFN␣ (5-1,000 IU/ml) in the presence and absence of dexamethasone (10 nM) and ascorbate (100 µM), which are agents known to affect osteogenic differentiation. IFN␣ produced a significant dose-dependent inhibition of cell proliferation and alkaline phosphatase specific activity at concentrations as low as 50 IU/ml. IFN␣ (50-1,000 IU/ml) inhibited the stimulation of alkaline phosphatase specific activity induced by ascorbate and dexamethasone. Examination of CFU-F showed dose-and time-dependent inhibitions of colony formation and reductions in both colony size and alkaline phosphatase-positive CFU-F colonies particularly at earlier times. Reactivity with an antibody specific for osteoprogenitors (HOP-26), was reduced in IFN␣-treated cultures. Northern blot analysis showed a significant dose-dependent up-regulation of BMP-2 mRNA, estrogen receptor alpha mRNA and osteocalcin mRNA expression in ascorbate/dexamethasone cultures. In contrast, IFN␣ significantly inhibited BMP-2 mRNA expression in the absence of ascorbate and dexamethasone. In conclusion, IFN␣ inhibits human osteoprogenitor cell proliferation, CFU-F formation, HOP-26 expression, and alkaline phosphatase specific activity and modulates BMP-2 gene expression. These results suggest a role for IFN␣ in local bone turnover through the specific and direct modulation of osteoprogenitor proliferation and differentiation.

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Domains of Interaction between Alpha Interferon and its Receptor Components

Cited by 108 publications

References 0 publications

The interferon gene cluster: a candidate region for MS predisposition?

The interferon gene cluster: a candidate region for MS predisposition?

Differences in Activity between α and β Type I Interferons Explored by Mutational Analysis

Effects of interferon alpha on human osteoprogenitor cell growth and differentiation in vitro

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