COMMUNICATION
Differential Use of the beta L Subunit of the Type I Interferon (IFN) Receptor Determines Signaling Specificity for IFNalpha 2 and IFNbeta *

Paul DomanskiDagger , Owen W. NadeauDagger , Leonidas C. Platanias§, Eleanor Fish, Merrill Kellumpar , Paula Pithapar , and Oscar R. ColamoniciDagger **

From the Dagger  Department of Pathology, University of Tennessee, Memphis, Tennessee 38163, the § Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago and West Side Veterans Affairs Hospital, Chicago, Illinois 60607, the  Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the par  Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

The signaling specificity for cytokines that have common receptor subunits is achieved by the presence of additional cytokine-specific receptor components. In the type I interferon (IFN) family, all 14 subtypes of IFNalpha , IFNbeta , and IFNomega bind to the same alpha  and beta L subunits of the type I IFN-R, yet differences in signaling and biological effects exist among them. Our data demonstrate that IFNalpha 2 and IFNbeta utilize different regions of the beta L subunit for signaling. Thus, in contrast to other cytokine systems, signal diversity in the type I IFN system can be accomplished within the same receptor complex by utilizing different regions of the same receptor subunits.

    INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Ligand binding to a receptor induces oligomerization of receptor subunits, which results in activation of various signaling pathways. Specificity in ligand receptor systems is achieved at the extracellular level by the specific interaction of a ligand with its distinct receptor components and at the intracellular level by the interaction of the cytoplasmic domain of the receptor subunits with a distinct set of signal transducing proteins. Many cytokine systems share receptor subunits (1-3), and in these situations it is commonly accepted that specificity is determined by the existence of additional ligand-specific receptor chains. For instance, the IL2R1 has a binding subunit (alpha  chain) and two signaling chains designated as beta  and gamma c. The IL2Rgamma c chain is also common to the IL4, IL7, and IL9 receptors and functions in association with specific receptor subunits for each of these cytokines (i.e. IL4Ralpha , IL7Ralpha , and IL9Ralpha chains). Therefore, these cytokines have the ability to produce both redundant and distinct biological effects (1-3).

The type I interferon (IFN) family includes 14 subtypes of IFNalpha , as well as one IFNbeta and IFNomega , all of which bind to the same cell surface receptor designated as IFNalpha R, IFNalpha beta R, or type I IFN-R (4). The type I IFN-R is composed of at least two subunits: the alpha  chain or IFNAR1 (5-9) and the beta  subunit or IFNAR2, which has short (beta S) and long (beta L) forms (10-14). Although expression of the alpha  chain with either beta L or beta S produces high affinity receptors in murine L-929 cells, only coexpression of alpha  and beta L allows activation of the Jak-Stat pathway and induction of an antiviral state in response to stimulation by both huIFNalpha 2 and huIFNbeta (13, 14). Interestingly, although both of these human IFNs bind to the same receptor and activate the same components of the Jak-Stat pathway, there are some signaling and biological differences. IFNbeta signaling has two distinctive features: (i) induction of a very strong association of the alpha  and beta L subunits of the type I IFN-R (15) and (ii) transcriptional activation of the beta -R1 gene (16). These signaling differences could be responsible for the disparity in biological effects among the members of the IFNalpha family. For example, IFNbeta is more effective than other type I IFNs in the treatment of multiple sclerosis (17, 18). However, unlike other cytokines, the differences in signaling and biological activities between IFNalpha and IFNbeta do not appear to result from the utilization of different receptor subunits. This has been demonstrated by the finding that mouse L-929 cells stably expressing the human alpha  and beta L subunits respond equally well to the induction of an antiviral state by huIFNalpha and huIFNbeta (13), and yet only IFNbeta triggers the aforementioned association of the alpha  and beta L chains (15).

In this report we show that IFNalpha 2 and IFNbeta require distinct intracytoplasmic regions of the beta L chain to elicit an antiviral response. L-929 cells expressing beta L truncated at amino acid 417 show a marked decrease in the antiviral response to IFNbeta but not to IFNalpha 2. However, no differences in the activation of ISGF3 or SIF factors by IFNalpha 2 or IFNbeta were detected. These data suggest that other signaling components, in addition to the Stat pathway, should be activated to obtain an antiviral response. Moreover, IFNbeta seems to activate this unknown pathway through a distinct mechanism that requires the 417-462 region of the beta L subunit.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

IFNs, Antibodies, and Antiviral Assays-- Human recombinant IFNalpha 2 and IFNbeta were kindly provided by Drs. Paul Trotta (Schering-Plow) and S. Goelz (Biogen). The anti-phosphotyrosine antibody (4G10) was obtained from Upstate Biotechnology Inc. (Lake Placid, NY). Monoclonal antibodies against Jak1 and Stat1 were purchased from Transduction Labs. (Lexington, KY). The anti-Stat1 and anti-Stat2 and anti-Jak1 sera were kindly provided by Drs. A. Larner (Food and Drug Administration, Bethesda, MD) and J. N. Ihle (St. Jude's Children's Hospital, Memphis, TN), respectively. Antiviral assays were performed as described previously (19).

Expression of Different Deletions of the beta L Subunit of Type I IFN-R in Mouse L-929 Cells-- These constructs were made by polymerase chain reaction using proofreading Vent polymerase and primers with an early termination codon at positions 346, 417, and 462 (see Fig. 1), respectively (20). Transfectants were grown in medium containing G-418 (500 µg/ml) and hygromycin B (500 µg/ml).

Immunoblotting-- Cells were treated with different concentrations of the indicated IFNs for 15 min, rapidly centrifuged at 2000 × g for 30 s in an Eppendorf microfuge, and subsequently solubilized in lysis buffer (20 mM Tris, pH 7.5, 50 mM NaCl, 10 mM sodium pyrophosphate, 20 mM NaF, 1 mM EDTA, 1 mM MgCl2, 1 mM dithiothreitol, 0.5% Triton X-100, 10 µg/ml leupeptin, 10 µg/ml aprotinin, 100 mM phenylmethylsulfonyl fluoride, 200 µM sodium orthovanadate). Immunoprecipitation and immunoblotting were performed as described previously (7).

Radioiodination of Type I IFNs, Competitive Displacements, and Affinity Cross-linking-- Radioiodination of IFNalpha 2 and competitive displacement assays were performed as described previously (6).

EMSA-- Whole cell extracts were prepared as described by Ghislain and Fish (21) and analyzed by EMSA using end labeled ISRE oligonucleotides to detect ISGF3.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

We hypothesized that the differences observed between IFNalpha and IFNbeta signaling occur within the same receptor complex and not by an additional ligand-specific subunit as in other cytokine systems (1-3). Such a model assumes that a particular subtype of the IFN family will use regions of the receptor complex that are not used by another subtype. Thus, we studied the ability of huIFNalpha 2 and huIFNbeta to induce an antiviral state in mouse L-929 cells stably coexpressing the wild type alpha  subunit with a beta L chain truncated at amino acid 462, 417, or 346, respectively (Fig. 1). All cell lines established were able to respond to huIFNalpha 2 as well as to muIFNalpha beta (positive control), indicating that the transfected receptor and the IFNalpha signaling pathway are functional. However, cells expressing the beta L chain truncated proximal to amino acid 462 (Table I, alpha beta L417.7, alpha beta L417.9, alpha beta L346.2, and alpha beta L346.4 cells) required significantly higher amounts of huIFNbeta to obtain 50% protection against encephalomyocarditis virus.


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Fig. 1.   Schematic representation of the human alpha  and beta L chain constructs expressed in mouse L-929 cells. The different interactions of the cytoplasmic domain of the beta L subunit are indicated. Constructs were made by polymerase chain reaction using primers with stop codons at the indicated positions (20). The binding sites for the Tyk2 and Jak1 kinases are shown (7, 20, 33). Transfectants were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and selection drugs (500 µg/ml of hygromycin and 500 µg/ml of geneticin).

                              
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Table I
Induction of an antiviral state by huIFNalpha 2 and huIFNbeta in L-929 cells expressing truncations of the beta L subunit and wild type alpha  chain
Cytopathic effect assay was performed using a concentration of encephalomyocarditis virus stock that produced 100% cytopathic effect. The IFN concentrations (units/ml) shown represent the amount of IFN required to inhibit cytopathic effect by 50%.

To demonstrate that the differences in the response to IFNalpha 2 and IFNbeta were not due to alterations in IFNbeta binding, we tested the ability of unlabeled IFNalpha 2 and IFNbeta to displace radioiodinated IFNalpha 2 from the human receptor subunits in the alpha beta L417 and alpha beta L462 cell lines. If the defect in the induction of an antiviral state by IFNbeta was a consequence of impaired binding of this IFN to the receptor, then unlabeled huIFNbeta should be less effective as a competitor for binding of 125I-IFNalpha 2 to the receptor than unlabeled IFNalpha 2. Fig. 2 shows that in alpha beta L417.7 and alpha beta L462.2 cells, unlabeled IFNbeta was even more effective in displacing 125I-IFNalpha 2 from the receptor than equivalent concentrations of unlabeled IFNalpha 2. Thus, the lack of induction of an antiviral state by IFNbeta in alpha beta L417 cells is not due to impaired recognition of the receptor by this IFN but rather by deletion of the 417-462 region of beta L, indicating that this region may contain a specific IFNbeta response element.


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Fig. 2.   Expression of beta L chain truncated at amino acid 417 does not affect binding of huIFNbeta to the receptor. Increasing concentrations of unlabeled huIFNalpha 2 or huIFNbeta (kindly provided by Drs. P. Trotta and S. Goelz, respectively) were used to displace binding of radioiodinated IFNalpha 2 to the receptor expressed in alpha beta L417.7 and alpha beta L462.2 cells. The Kd values in alpha beta L417.7 cells were 33 and 5 pM for IFNalpha 2 and IFNbeta , respectively. In alpha beta L462.2 cells the Kd values were 48 and 40 pM for IFNalpha 2 and IFNbeta , respectively. Affinities were calculated using the computer program LIGAND (34). Radioiodinated huIFNalpha 2 was selected for these experiments, because it labels to a higher specific activity (96 µg/µCi) than huIFNbeta and can induce an antiviral state in alpha beta L417 and alpha beta L462 cells.

To further examine the differences observed in the antiviral response, time course and dose response experiments were performed in alpha beta L417.7 and alpha beta L462.2 cells to determine the length and intensity of tyrosine phosphorylation for components of the Jak-Stat pathway. Fig. 3A shows that IFNbeta (lanes 3, 5, and 7) induced even higher levels of Jak1 tyrosine phosphorylation than IFNalpha 2 (lanes 1, 4, and 6) in alpha beta L417.7 cells at all time points studied. Intense phosphorylation could be detected at 10 min and returned to base-line levels by 90 min. Dose response experiments showed that activation of Jak1 was achieved at doses as low as 300 units/ml of IFNalpha 2 or IFNbeta (Fig. 3A, lower panel, lanes 2-5). Similar results were obtained in time course and dose response experiments performed with alpha beta L462.2 (data not shown). We also studied the activation of Tyk2 kinase in both cell lines. Fig. 3B shows that Tyk2 tyrosine phosphorylation was induced by both IFNalpha 2 and IFNbeta in alpha beta L417.7 and alpha beta L462.2 cells at 10 min (lanes 2, 3, 9, and 10) and subsequently decreased at 30 min (lanes 4, 5, 11, and 12). The level of Tyk2 phosphorylation returned to base-line levels by 90 min in alpha beta L462.2 cells (lanes 13 and 14) and significantly decreased in alpha beta L417.7 cells (lanes 6 and 7). Tyk2 tyrosine phosphorylation was also detected with concentrations of IFNalpha 2 or IFNbeta as low as 300 units/ml (Fig. 3C, lanes 2, 3, 7, and 8). It is worth mentioning that the level of tyrosine phosphorylation detected in alpha beta L462 cells were slightly higher than in alpha beta L417 cells (Fig. 3C, compare alpha beta L417 and alpha beta L462 cells).


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Fig. 3.   Activation of the Jak-Stat pathway in response to huIFNalpha 2 and huIFNbeta . A, cells were stimulated with huIFNalpha 2 or huIFNbeta (20,000 units/ml) for the indicated periods of time (top panel) or for 10 min with the indicated concentrations of IFN (bottom panel). Cell lysates were immunoprecipitated with an anti-Jak1 serum, resolved in a 8% SDS-polyacrylamide gel electrophoresis, immunoblotted with the anti-phosphotyrosine antibody 4G10, stripped, and reblotted with an anti-Jak1 monoclonal antibody (Transduction Laboratories). B, tyrosine phosphorylation of Tyk2 in response to IFNalpha 2 or IFNbeta . Cells were treated as described in A, immunoprecipitated with an anti-Tyk2 antibody, and immunoblotted with the anti-phosphotyrosine antibody 4G10. Stripping and immunoblotting of the same filter with the anti-Tyk2 serum could not be performed due to the high background produced by this antibody when used for immunoblotting as described previously (13). C, experiment similar to that in B in which lower doses of IFNs were used. Cellular lysates were immunoprecipitated with an anti-Tyk2 antibody and immunoblotted with the anti-phosphotyrosine antibody 4G10. The electrophoretic mobility of Tyk2 and a background protein (Bkgd) detected in some experiments are indicated. IP, immunoprecipitation; WB, Western blot; CT, control.

We next studied the activation of the Stat proteins. Fig. 4 shows that at all time points studied there were no differences in the induction of tyrosine phosphorylation of Stat1 by IFNalpha 2 or IFNbeta in alpha beta L417.7 (panel A) or alpha beta L462.2 (panel B) cells. Tyrosine phosphorylation was maximal at 30 min and then progressively declined. Fig. 4 (A and B) also shows that after IFNalpha 2 or IFNbeta treatment the anti-Stat1 serum coimmunoprecipitates another tyrosine phosphorylated protein that has an electrophoretic mobility similar to that of Stat2. The lower panels in A and B of Fig. 4 show that equivalent amounts of Stat1 were immunoprecipitated in all conditions. Similar results were obtained when the activation of Stat1 and Stat2 (ISGF3) was studied by EMSA with an ISRE probe. Fig. 4C shows that equivalent levels of the ISGF3 were induced by huIFNalpha 2 and huIFNbeta in alpha beta L417.7 cells even though these cells are resistant to the induction of an antiviral state by huIFNbeta but remain sensitive to IFNalpha 2. Similar results were observed with alpha beta L462.2 cells (Fig. 4C, lower panel). Dose response experiments were then performed to examine the ability of varying concentrations of huIFNalpha 2 or huIFNbeta to affect activation of Stat proteins. Fig. 4D shows that Stat1 and Stat2 activation are equivalent for human IFNalpha and IFNbeta at concentrations as low as 300 units/ml. The higher levels of tyrosine phosphorylation observed after treatment with 300 units/ml of IFNalpha or IFNbeta in alpha beta L462 cells are likely due to the higher amounts of Stat1 protein precipitated in these lanes (Fig. 4D, lower panel, anti-Stat1 immunoblot). The middle panel in Fig. 4D shows an immunoblot with an anti-Stat2 antibody that identifies Stat2 as the protein coprecipitated by the anti-Stat1 antibody. Coprecipitation of Stat2 is proportional to the intensity of tyrosine phosphorylation as expected from a SH2-phosphotyrosine interaction. In summary, the study of activation of the Jak kinases and Stat factors in alpha beta L417 and alpha beta L462 cells did not reveal significant differences that would account for the impaired response to IFNbeta observed in alpha beta L417 cells.


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Fig. 4.   Activation of Stat proteins by IFNalpha and IFNbeta . A and B, time course experiments. Antiphosphotyrosine immunoblotting (upper panels) were performed as described in Fig. 3, but immunoprecipitations were performed with an anti-Stat1 antibody instead. The same filters was stripped and then probed with anti-Stat1 antibody (lower panels) to determine the amounts of Stat1 protein loaded in each lane. C, EMSA to detect ISGF3 induction. Whole cell extracts were obtained from alpha beta L417.7 and alpha beta L462.2 transfectants treated with huIFNalpha 2 (20,000 units/ml), huIFNbeta (20,000 units/ml), or left untreated for the indicated times at 37 °C as described previously (21). EMSA was performed using an ISRE probe (21) for the detection of the ISGF3 (arrows). D, dose response experiment. Tyrosine phosphorylation of Stat1 and Stat2 was studied after stimulation of alpha beta L417.7 and alpha beta L462.2 cells with different concentrations of huIFNalpha 2 and huIFNbeta . Cell protein homogenates were immunoprecipitated with anti-Stat1 serum and then sequentially immunoblotted with anti-phosphotyrosine (upper panel), anti-Stat2 (middle panel), and anti-Stat1 (lower panel) antibodies.

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Cytokine systems that share subunits usually show both overlapping and distinct biological effects that result from activation of common and discrete receptor chains, respectively (3). In the type I IFN system, however, several lines of evidence indicate that the different subtypes of IFNalpha , IFNbeta , and IFNomega utilize a common type I IFN-R. For example, all type I IFNs compete for binding to the same receptor (reviewed in Refs. 4 and 22) and specific monoclonal antibodies that recognize the alpha  and beta chains, block binding, and inhibit biological activity of several type I IFNs (11, 23). Other anti-alpha subunit antibodies precipitate radiolabeled huIFNalpha 2, huIFNalpha 7, huIFNalpha 8, huIFNbeta , and huIFNomega cross-linked to the alpha  subunit (24). Finally, expression of the human wild type alpha  and beta L subunits in mouse L-929 cells gives them the ability to mount an antiviral response after treatment by either huIFNalpha 2 or huIFNbeta (13). Our data for the type I IFN system indicate that binding of different ligands to the same receptor chains produces changes that go beyond simple dimerization of receptor subunits. IFNalpha 2 and IFNbeta apparently utilize different regions of the intracellular domain of the beta L subunit to generate an antiviral state. One possible explanation is that each IFN promotes distinct conformational changes in the receptor that affects signaling through the 417-462 region of beta L, similar to the mechanism proposed for the Tar protein (25, 26). This model theoretically increases the number of distinct biological responses that can be promoted by different ligands utilizing a common set of receptor subunits, which may explain how different type I IFNs exert slightly different biological responses (27). The presence of two binding sites on the alpha  subunit of the type I IFN-R receptor (28) may contribute to the diverse biological responses induced by different subtypes of type I IFNs. This is supported by the finding that the splice variant of the alpha  subunit, which lacks the N-terminal binding site, preferentially binds certain type I IFNs (29).

Finally, the differences in induction of an antiviral state by IFNalpha and IFNbeta do not correlate with differences in activation of the Jak-Stat pathway. This is not surprising because mutant U4 cells complemented with kinase deficient Jak1 can induce IFNgamma -activating factor and the interferon-stimulated gene but not an antiviral state in response to IFNgamma (30). Therefore, although activation of these DNA binding complexes is required (31, 32), it is not sufficient to elicit an antiviral effect. Similarly, the IFNbeta response is partially conserved in mutant cells that lack Tyk2 (35, 36). These findings suggest that additional signaling mechanisms should be triggered by IFNs. It is tempting to speculate that the IFNbeta -induced activation of the IFNbeta response element (IBR) region of beta L is responsible for the formation of other DNA binding complexes that interact with an element different from the ISRE or IRE. The existence of such elements has been also proposed by others to explain the differences in induction of the IFNbeta -specific gene beta R-1 (16).

    ACKNOWLEDGEMENTS

We thank Dr. J. N. Ihle for providing us with the anti-Jak1 serum and Dr. Andrew Larner for the anti-Stat1 and anti-Stat2 sera.

    FOOTNOTES

* This work was supported by National Institutes of Health Grants CA55079 and GM54709 (to O. R. C.) and CA73381 (to L. C. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Pathology, University of Tennessee, 899 Madison Ave., M-576, Memphis, TN 38163. Tel.: 901-448-6173; Fax: 901-448-6979; E-mail: OColamonici{at}utmem1.utmem.edu.

1 The abbreviations used are: IL, interleukin; IL2R, IL-2 receptor; IFN, interferon; IFN-R, IFN receptor; Stat, signal transducer and activator of transcription; ISGF3, interferon-stimulated gene factor 3; EMSA, electrophoretic mobility shift assay.

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Abstract
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Materials & Methods
Results
Discussion
References

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