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At least 19 recordsLinked to original sources
PubMed1994

Tyrosine phosphorylation of the alpha and beta subunits of the type I interferon receptor. Interferon-beta selectively induces tyrosine phosphorylation of an alpha subunit-associated protein.

We studied the phosphorylation of the alpha and beta subunits of the Type I interferon (IFN) receptor induced by Type I IFNs in the human U-266 and MOLT-4 cell lines. Both IFN-alpha and IFN-beta induced tyrosine phosphorylation of the beta subunit of the receptor. The Type I IFN-induced tyrosine phosphorylation of the beta subunit was rapid and transient, being detectable within 1 min of Type I IFN treatment and gradually diminishing to almost base-line levels by 60 min. All Type I IFNs studied were found to induce tyrosine phosphorylation of the alpha subunit of the Type I IFN receptor, the p135tyk2 and JAK-1 tyrosine kinases, and the ISGF3 alpha components. Interestingly, IFN-beta, but not IFN-alpha or IFN-omega, induced tyrosine phosphorylation of an alpha subunit-associated protein with an apparent molecular mass of approximately 100 kDa (p100). These data suggest the existence of a common signaling pathway(s) for Type I IFNs involving the alpha and beta subunits of the receptor, the tyrosine kinases p135tyk2 and JAK-1, and the ISGF3 alpha components. However, differences between the signaling pathways of different Type I IFNs exist, as suggested by tyrosine phosphorylation of an alpha subunit-associated protein only in response to IFN-beta.

Humans↗
PubMed1996

Differential responsiveness of a splice variant of the human type I interferon receptor to interferons.

Chinese hamster ovary cells containing the yeast artificial chromosome F136C5 (alphaYAC) respond to all type I human interferons including IFN-alphaA, IFN-beta, and IFN-omega. The alphaYAC contains at least two genes encoding interferon-alpha receptor (IFN-alphaR) chains that are required for response to type I human interferons: Hu-IFN-alphaR1 and Hu-IFN-alphaR2. We previously isolated a splice variant of the Hu-IFN-alphaR1 chain designated Hu-IFN-alphaR1s. Chinese hamster ovary cells containing a disrupted alphaYAC, which contains a deletion in the human IFNAR1 gene, were transfected with expression vectors for the Hu-IFN-alphaR1 and Hu-IFN-alphaR1s chains. With these cells, two type I interferons have been identified which can interact with the splice variant (Hu-IFN-alphaR1s) and with the Hu-IFN-alphaR1 chains: Hu-IFN-alphaA and IFN-omega. Two other type I interferons, Hu-IFN-alphaB2 and Hu-IFN-alphaF, are capable of signaling through the Hu-IFN-alphaR1 chain only and cannot utilize the splice variant Hu-IFN-alphaR1s. Hu-IFN-alphaR1 and Hu-IFN-alphaR1s differ in that the latter is missing a single subdomain of the receptor extracellular domain encoded by exons 4 and 5 of the IFNAR1 gene. These results therefore indicate that different type I interferons require different subdomains of the Hu-IFN-alphaR1 receptor chain, and that the splice variant chain (Hu-IFN-alphaR1s) is functional.

Amino Acid Sequence↗
PubMed1995

Differential recognition of the type I interferon receptor by interferons tau and alpha is responsible for their disparate cytotoxicities.

Interferon tau (IFN tau), originally identified as a pregnancy recognition hormone, is a type I interferon that is related to the various IFN alpha species (IFN alpha s). Ovine IFN tau has antiviral activity similar to that of human IFN alpha A on the Madin-Darby bovine kidney (MDBK) cell line and is equally effective in inhibiting cell proliferation. In this study, IFN tau was found to differ from IFN alpha A in that is was > 30-fold less toxic to MDBK cells at high concentrations. Excess IFN tau did not block the cytotoxicity of IFN alpha A on MDBK cells, suggesting that these two type I IFNs recognize the type I IFN receptor differently on these cells. In direct binding studies, 125I-IFN tau had a Kd of 3.90 x 10(-10) M for receptor on MDBK cells, whereas that of 125I-IFN alpha A was 4.45 x 10(-11) M. Consistent with the higher binding affinity, IFN alpha A was severalfold more effective than IFN tau in competitive binding against 125I-IFN tau to receptor on MDBK cells. Paradoxically, the two IFNs had similar specific antiviral activities on MDBK cells. However, maximal IFN antiviral activity required only fractional occupancy of receptors, whereas toxicity was associated with maximal receptor occupancy. Hence, IFN alpha A, with the higher binding affinity, was more toxic than IFN tau. The IFNs were similar in inducing the specific phosphorylation of the type I receptor-associated tyrosine kinase Tyk2, and the transcription factors Stat1 alpha and Stat2, suggesting that phosphorylation of these signal transduction proteins is not involved in the cellular toxicity associated with type I IFNs. Experiments using synthetic peptides suggest that differences in the interaction at the N terminal of IFN tau and IFN alpha with the type I receptor complex contribute significantly to differences in high-affinity equilibrium binding of these molecules. It is postulated that such a differential recognition of the receptor is responsible for the similar antiviral but different cytotoxic effects of these IFNs. Moreover, these data imply that receptors are "spare'' with respect to certain biological properties, and we speculate that IFNs may induce a concentration-dependent selective association of receptor subunits.

Animals↗
PubMed2006

Intrahepatic mRNA levels of type I interferon receptor and interferon-stimulated genes in genotype 1b chronic hepatitis C. Association between IFNAR1 mRNA level and sustained response to interferon therapy.

OBJECTIVE: The aim of this study was to determine the association between pretreatment intrahepatic mRNA levels of interferon receptor and interferon-stimulated genes and response to interferon therapy for genotype 1b chronic hepatitis C. METHODS: Forty-four patients with genotype 1b chronic hepatitis C who underwent liver biopsy and then received interferon therapy participated in this study. Pretreatment intrahepatic mRNA levels of interferon receptor genes (IFNAR1, IFNAR2b, and IFNAR2c) and interferon-stimulated genes (OAS1 and PKR) were quantified by competitive polymerase chain reaction. RESULTS: In the genes examined, only IFNAR1 mRNA level was significantly higher in patients with sustained virological and biochemical response to interferon therapy versus those with nonsustained response (p < 0.01). Moreover, mRNA expression ratios of IFNAR1 to IFNAR2 were also significantly higher in patients with sustained virological and biochemical response to IFN therapy (p < 0.01 and p < 0.05, respectively). On the other hand, mRNA levels of IFNAR2b, IFNAR2c, and PKR were significantly higher in patients with histologically active or advanced liver rather than patients with mild or less advanced liver. CONCLUSIONS: High intrahepatic mRNA levels of IFNAR1 and mRNA ratio of IFNAR1 to IFNAR2 before treatment may be associated with a favorable response to interferon therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Hydrophobic cluster analysis reveals duplication in the external structure of human alpha-interferon receptor and homology with gamma-interferon receptor external domain.

Evidence is presented, based on sequence comparison according to Hydrophobic Cluster Analysis, of a structural and evolutionary relationship between the human alpha/beta-interferon receptor and the human and mouse gamma-interferon receptor. These results predict that the human alpha/beta-interferon receptor extracellular part is organised in two homologous subdomains connected by a proline linker. They also predict that both subdomains present some homologies to the external domain of mouse and human gamma interferon receptor.

Amino Acid Sequence↗
PubMed1999

Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation.

Human type I interferons (IFN) require two receptor chains, IFNAR1 and IFNAR2c for high affinity (pM) binding and biological activity. Our previous studies have shown that the ligand dependent assembly of the type I IFN receptor chains is not identical for all type I IFNs. IFNbeta appears unique in its ability to assemble a stable complex of receptor chains, as demonstrated by the observation that IFNAR2c co-immunoprecipitates with IFNAR1 when cells are stimulated with IFNbeta but not with IFNalpha. The characteristics of such a receptor complex are not well defined nor is it understood if differential signaling events can be mediated by variations in receptor assembly. To further characterize the factors required for formation of such a stable receptor complex we demonstrate using IFN stimulated Daudi cells that (1) IFNAR2c co-immunoprecipitates with IFNAR1 even when tyrosine phosphorylation of receptor chains is blocked with staurosporine, and (2) IFNbeta1b but not IFNalpha2, is present in the immunoprecipitated receptor complex. These results demonstrate that the unique IFNbeta induced assembly of type I IFN receptor chains is independent of receptor tyrosine phosphorylation and the recruitment of additional proteins to the receptor by such events. Furthermore, the presence of IFNbeta1b in the immunoprecipitated IFN receptor complex suggests that IFNbeta interacts and binds differently to the receptor than IFNalpha2. These results suggest that the specific assembly of type I IFN receptor chains is ligand dependent and may represent an early event which leads to the differential biological responses observed among type I IFNs.

Humans↗
PubMed2005

Expression of the type I interferon receptor and the interferon-induced Mx protein in human endometrium during the menstrual cycle.

OBJECTIVE: To investigate the expression of the type I interferon receptor (IFNAR) and interferon-induced Mx protein (Mx) in normal human endometrium throughout the menstrual cycle. DESIGN: Prospective study. SETTING: Medical university in Japan. PATIENT(S): Thirty-seven normal endometrial tissues from fertile women who had undergone hysterectomies for reasons other than endometrial disease. INTERVENTION(S): IFNAR-1, IFNAR-2, MxA, and MxB gene expression was analyzed by reverse transcription-real-time quantitative polymerase chain reaction. Moreover, localization of IFNAR-1 and IFNAR-2 were studied by immunohistochemistry. MAIN OUTCOME MEASURE(S): Expression of IFNAR-1, IFNAR-2, MxA, and MxB. RESULT(S): Expression of IFNAR-2 gene was significantly increased in the menstrual and midsecretory phase as compared with in the proliferative phase. Immunohistochemistry for IFNAR-1 and IFNAR-2 revealed weak staining of glandular epithelium and weak staining of stromal cells during the proliferative phase. However, an intense immunohistochemical staining of IFNAR-2 was observed on the surface and basement membrane of glands in the secretory phase. There was no statistical difference between MxA and MxB gene expression throughout the menstrual cycle. CONCLUSION(S): Our results suggest that IFNAR and Mx are expressed in the human endometrium and that the expression of IFNAR is cyclically changed during the menstrual cycle.

Endometrium↗
PubMed1991

Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis.

Sequence comparison based on Hydrophobic Cluster Analysis procedures shows that the extracellular approximately 200 amino acids domains of cytokines receptors belonging to the Cytokine/Growth hormone/Prolactin receptor family and to the Interferon one are organized in two homologous subdomains. Further, comparison of the subdomains of 32 independent sequences and of a lot of already recognized homologous domains with data bases could lead to the hypothesis that these approximately 100 amino acids subdomains could possess the overall fold of the constant immunoglobulin domains and so could belong to the immunoglobulin superfamily.

Amino Acid Sequence↗
PubMed1996

The human type I interferon receptor. Identification of the interferon beta-specific receptor-associated phosphoprotein.

We used specific antibodies recognizing the receptor 1 (IFNAR1) and the recently cloned receptor 2.2 (IFNAR2.2) chains of the human type I interferon receptor complex to demonstrate that the interferon beta (IFN-beta)-specific receptor-associated phosphoprotein is IFNAR2.2 and not an unknown or additional receptor component. Immunoprecipitation experiments demonstrated that IFNAR2.2 is present in Daudi cells as a cell surface protein of approximately 90-100 kDa, which is tyrosine-phosphorylated and associated with IFNAR1, upon stimulation of cells with IFN-beta. IFNAR2.2 was not detected associated with IFNAR1 in cells stimulated with IFN-alpha, suggesting differences in receptor interaction between the two type I interferons. Both IFNAR1 and IFNAR2.2 undergo tyrosine phosphorylation upon induction by either IFN-alpha or IFN-beta. Therefore, it is unclear as to why IFNAR2.2 is not detectable in IFNAR1 immunoprecipitates in IFN-beta-treated cells. These data suggest that, although IFN-alpha and IFN-beta may utilize similar receptor chains, they interact with IFNAR1 and IFNAR2.2 in different ways.

Baculoviridae↗
PubMed1995

Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors.

Alpha/beta interferon (IFN) and gamma IFN exert widely overlapping biological effects. Still, mice with individually inactivated alpha/beta or gamma receptors exhibit variably severely reduced resistance to infection and altered immune responses. To investigate to what extent the two IFN systems are functionally redundant, we generated mice with a combined receptor defect (AG129 mice). Like mice with individual mutations, AG129 mice had no apparent anomalies, confirming that in the mouse the IFN system is not essential for normal development. These mice showed an additive phenotype with respect to antiviral defense and exhibited an increased susceptibility to lymphocytic choriomeningitis virus (LCMV) and notably vaccinia virus infection. Because of unlimited replication and subsequent rapid exhaustion of cytotoxic T lymphocyte (CTL) precursors, these mice were unable to mount a CTL response to LCMV. CD8(+)-mediated immunopathology was absent in LCMV-infected mice, and virus persisted. Vaccinia virus replicated much faster in AG129 mice, and a 10(4)-fold lower dose of vaccinia virus was sufficient to prime these mice. With the normal priming dose of 10(6) PFU, cytopathic effects and overwhelming infection possibly causing partial exhaustion of CTL interfered with the anti-vaccinia virus response. Even though global antiviral immunoglobulin G (IgG) titers were within normal ranges, the IgG subclass distribution was heavily biased toward IgG1.

Animals↗
PubMed1984

Interferon receptor interaction. Internalization of interferon alpha 2 and modulation of its receptor on human cells.

Studies reported earlier [ Joshi et al. (1982) J. Biol. Chem. 257, 13884-13887] have indicated that human interferon-alpha 2 (HuIFN-alpha 2) binds to a specific macromolecular receptor on human cells as identified by cross-linking with bifunctional cross-linking reagents and analysis by polyacrylamide gel electrophoresis. We have carried out experiments to investigate the fate of the interferon-receptor complex on the cell surface under conditions which lead to cellular response. As analyzed by cross-linking and gel electrophoresis, the interferon-receptor complex, formed on incubation with 125I-IFN-alpha 2 at 4 degrees C, persisted at the cell surface for several hours at 4 degrees C; however, if the cells were switched to 37 degrees C, there was a rapid decline in the complex, apparently due to a loss of the interferon receptors from the cell surface. This was associated with an internalization of the 125I-interferon as indicated by the fact that, on incubation at 37 degrees C, an appreciable fraction of the cell-associated interferon (approximately equal to 50%) became resistant to trypsin digestion, or dissociation on incubation in growth medium or low-pH buffer. A large fraction of the trypsin-resistant (internalized) 125I-labeled material migrated as intact interferon in polyacrylamide gels, and it was immunoprecipitated by anti-(HuIFN-alpha)antibodies but not by anti-(HuIFN-beta)antibodies. The bulk of the internalized 125I-interferon was recovered in a particulate fraction and, on cross-linking with disuccinimidyl suberate, a 150000-Mr complex could be detected. The results suggest that interferon may be internalized as a complex with the receptor, which may account for the loss of the interferon-receptors on the cell surface. This modulation of the IFN-alpha/beta receptors was induced by HuIFN-alpha and HuIFN-beta but not by HuIFN-gamma. The recovery of the IFN-alpha/beta receptors, lost upon incubation with HuIFN-alpha, took several hours and required protein synthesis. The significance of the results is discussed.

Burkitt Lymphoma↗
PubMed1987

Expression of gamma-interferon receptor in murine bone marrow-derived macrophages associated with macrophage differentiation: evidence of gamma-interferon receptors in the regulation of macrophage proliferation.

The effect of purified, recombinant murine gamma interferon (IFN-gamma) on the regulation of macrophage proliferation induced by colony-stimulating factor 1 (CSF-1) was investigated. Although both hemopoietic stem cells (GM-CFC) and tissue-derived peritoneal exudate macrophages (PEM) proliferated in response to CSF-1, the more mature PEM were much more sensitive to an antiproliferative effect of IFN-gamma. The role of IFN-gamma receptor expression and its relationship to growth inhibition was examined. Bone marrow cells as a whole did not exhibit an appreciable amount of IFN-gamma receptor binding activity. Likewise, nonadherent (NA) cells derived from CSF-1-stimulated bone marrow cultures displayed low levels of IFN-gamma receptor binding activity. On the contrary, more mature adherent (AD) cells (monocytes/macrophages) from the same culture exhibited high levels of IFN-gamma receptor binding activity, which continued to increase with culture time. The elevated IFN-gamma binding activity is due to an increase in total receptor number rather than the binding affinity as judged by Scatchard analysis. Similar to the relationship between PEM and GM-CFC, more mature AD cells were also more susceptible to the inhibitory effect of IFN-gamma on CSF-1-induced proliferation than their less mature NA counterparts. The fact that the sensitivity to IFN-gamma correlated well with the expression of existing IFN-gamma receptors strongly suggests that the inhibitory effect is mediated through IFN-gamma receptors. This study shows that the expression of IFN-gamma receptors in mononuclear phagocytes may not only represent one of the phenotypic parameters acquired by the growing macrophages during the process of differentiation, but may play some role in controlling proliferation.

Animals↗
PubMed2004

Type I interferon receptor and response to interferon therapy in chronic hepatitis C patients: a prospective study.

The type I interferon (IFN) receptor consists of at least two subunits, IFNAR1 and IFNAR2. We previously found a correlation between IFNAR1 and IFNAR2 expression in liver, and a correlation in IFNAR2 expression, but not in IFNAR1, between liver and peripheral blood mononuclear cells (PBMCs). The aim of this study was to prospectively assess whether IFNAR2 expression levels in PBMCs as well as in liver act as markers for predicting response to IFN therapy in chronic hepatitis C patients. Fifty-two Japanese patients with chronic hepatitis C, were enrolled. IFNAR2 mRNA was quantified using competitive polymerase chain reaction, in liver and PBMC specimens, and of the 52 patients assigned to receive a 6-month course of interferon-alpha therapy, 36 patients who received more than 300 million units of interferon were analysed. IFNAR2 mRNA expression levels were significantly higher in liver than in PBMCs in all 36 patients (P = 0.016). Seventeen sustained virologic responders showed lower pretreatment hepatitis C virus (HCV)-RNA levels (P = 0.017) in serum and higher pretreatment levels of IFNAR2 mRNA in liver (P = 0.007), but not in PBMCs, compared with nonsustained virologic responders. In multivariate analysis, these factors were independently associated with a sustained virologic response (i.e. HCV-RNA level: odds ratio 0.23, 95% CI 0.038-0.864; and IFNAR2 in liver: odds ratio 1.116, 95% CI 1.015-1.227). Hence, IFNAR2 expression levels in liver, but not in PBMCs, is predictive of response to IFN treatment in chronic hepatitis C patients.

Adult↗
PubMed1994

A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells.

Expression of the human interferon gamma receptor (IFN-gamma R) in mouse cells is not sufficient to confer biological responsiveness to human IFN-gamma and vice versa. An additional species-specific component is required for signal transduction. We identified this cofactor by expression cloning in simian COS cells stably transfected with the nonfunctional murine IFN-gamma R and a IFN-gamma-inducible reporter construct encoding the human Tac antigen (interleukin-2 receptor alpha chain, CD25). A cDNA clone was obtained that, upon stable transfection, rendered human HEp-2 cells expressing the murine IFN-gamma R fully responsive to murine IFN-gamma. This cDNA encodes a novel 332 amino acid type I transmembrane protein that belongs to the IFN receptor family and that we designate IFN-gamma R beta chain.

Amino Acid Sequence↗
PubMed2002

Temporal expression of type I interferon receptor in the peri-implantation ovine extra-embryonic membranes: demonstration that human IFNalpha can bind to this receptor.

Interferon-tau (IFNtau), produced by the trophectoderm of ruminant ungulates, binds to the type I IFN receptor (IFNAR) located at the uterine endometrium in a paracrine manner. Since IFNtau attenuates the secretory pattern of an endometrial luteolysin, prostaglandin F2alpha, IFNtau has been considered as a conceptus factor implicated in the process of maternal recognition of pregnancy. Here we report the presence of IFNAR subunit (IFNAR1) in ovine conceptuses during the period of peri-implantation development and demonstrate that 125I-human (h) IFNalpha binds to membrane preparations from ovine corpus luteum and conceptus. Using an antibody against hIFNAR1, immunohistochemical analysis revealed that IFNAR1 protein was present in day 14 and 16 conceptuses (day 0 = day of estrus) and luminal and glandular epithelia of the endometrium. Conceptus membrane proteins analyzed by western blot with the same antibody displayed immunoreactive bands at 95, 60 and 55 kDa while endometrial membrane proteins showed bands at 200, 95 and 55 kDa. Northern blot analysis revealed that IFNAR1 mRNA was present in days 15-19 conceptuses and day 18-19 allantoic membranes. Receptor binding studies indicated that 125I-hIFNalpha binding to day 16, but not earlier, conceptus membrane proteins could be displaced with hIFNalpha or ovine IFNtau. Based on Scatchard analysis, day 16 conceptus membranes contained 28 fmol IFNAR/mg protein with a dissociation constant of 300 pM. Cross-linking experiments demonstrated that 125I-hIFNalpha-receptor complex migrated at 120 kDa, indicating that the receptor component(s) was approximately 100 kDa. These data provide evidence that although the binding does not occur until day 16, ovine conceptuses possess IFNAR1 near or at the time of implantation, suggesting that IFNtau, a factor produced by the trophectoderm of ruminant ungulates, could act on the conceptus in an autocrine manner. In addition to functioning as an antiluteolytic factor, therefore, IFNtau may have a direct effect on conceptus development.

Animals↗
PubMed1994

Ligand-independent anti-oncogenic activity of the alpha subunit of the type I interferon receptor.

Two interferon (IFN) alpha-regulated genes, IRF1/ISGF2 and PKR/p68 kinase, may function as tumor suppressor genes suggesting that the IFN system may function as a tumor suppressor system. We report that the expression of the alpha subunit of the type I IFN receptor in human K-562 cells had anti-oncogenic effects that include a marked decrease in: (i) cell proliferation rate, (ii) the cell density at which growth arrest normally occurs, and (iii) the tumorigenicity in nude mice. Furthermore, expression of the alpha subunit in K-562 cells induced erythroid differentiation. While most cytokine receptors become activated after binding their corresponding ligands, the overexpression of the alpha subunit has a physiological effect in the absence of its natural ligand, type I IFNs, suggesting a novel function for this type I IFN receptor subunit. The anti-oncogenic effect of the alpha subunit is mediated by a pathway that does not involve two tumor suppressor genes induced by type I IFNs, the transcriptional regulator IFN response factor-1 and the RNA-dependent protein kinase, or the p135tyk2 tyrosine kinase that directly associates and phosphorylates the alpha subunit.

Animals↗