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Hybrid IFN Biological Responses to Recombinant Human Divergence Of Divergence of Binding, Signaling, and Biological Responses to Recombinant Human Hybrid IFN This information is current as Renqiu Hu, Joseph Bekisz, Mark Hayes, Susette Audet, Judy of September 24, 2021. Beeler, Emanuel Petricoin and Kathryn Zoon J Immunol 1999; 163:854-860; ; http://www.jimmunol.org/content/163/2/854 Downloaded from References This article cites 29 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/163/2/854.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Divergence of Binding, Signaling, and Biological Responses to Recombinant Human Hybrid IFN1 Renqiu Hu,2* Joseph Bekisz,* Mark Hayes,* Susette Audet,† Judy Beeler,† Emanuel Petricoin,* and Kathryn Zoon* Three human IFN-a hybrids, HY-1 [IFN-a21a(1-75)/a2c(76-165)], HY-2 [IFN-a21a(1-95)/a2c(96-165)], and HY-3 [IFN-a2c(1- 95)/a21a(96-166)], were constructed, cloned, and expressed. The hybrids had comparable specific antiviral activities on Madin- Darby bovine kidney (MDBK)3 cells but exhibited very different antiproliferative and binding properties on human Daudi and WISH cells and primary human lymphocytes. Our data suggest that a portion of the N-terminal region of the molecule is important for interaction with components involved in binding of IFN-a2b while the C-terminal portion of IFN is critical for antiproliferative activity. A domain affecting the antiproliferative activity was found within the C-terminal region from amino acid residues 75–166. The signal transduction properties of HY-2 and HY-3 were evaluated by EMSA and RNase protection assays. Downloaded from Both HY-2 and HY-3 induced activation of STAT1 and 2. However, HY-2 exhibited essentially no antiproliferative effects at concentrations that activated STAT1 and 2. Additionally, at concentrations where no antiproliferative activity was seen, HY-2 induced a variety of IFN-responsive genes to the same degree as HY-3. RNase protection assays also indicate that, at concentra- tions where no antiproliferative activity was seen for HY-2, this construct retained the ability to induce a variety of IFN-inducible genes. These data suggest that the antiproliferative response may not be solely directed by the activation of the STAT1 and STAT2 pathway in the cells tested. The Journal of Immunology, 1999, 163: 854–860. http://www.jimmunol.org/ nterferons are cytokines that have been shown to affect a To date, our laboratory has purified and characterized 22 IFN-a wide variety of cellular functions, including inhibition of cel- components produced by Sendai virus-induced human lympho- I lular proliferation, antiviral activity, immune regulatory func- blastoid cells (12). One of these species, component o, was found tions, and activation of multiple cellular genes (1). Antiviral and to be noteworthy for its high antiproliferative activity and its poor antiproliferative activities are clinically important properties of ability to compete with the IFN-a2b binding site (13). Based on IFN-as. Several types of IFN-a2 are currently approved for a va- our partial amino acid sequence data, component o was indistin- riety of diseases including hepatitis b and c, hairy cell leukemia, guishable from IFN-a21a. Therefore, rIFN-a21a was cloned and by guest on September 24, 2021 and chronic myelogenous leukemia (2). expressed. It was determined to behave functionally like compo- Recombinant techniques are useful methods for the production nent o in that it exhibits a high antiproliferative sp. act. and com- and modification of IFN-a proteins. The first IFN hybrid, IFN- petes poorly for the IFN-a2b binding site (13, 14). a1/a2 was constructed using recombinant technology in 1981 (3). The goals of our studies are to determine the specific region(s) Subsequently, a number of hybrids have been constructed and have of IFN-a21a responsible for the enhanced antiproliferative activity been informative for examining the activity of IFNs (4–11). These and to further understand the signaling mechanism it uses to elicit hybrid constructs have resulted in novel IFNs that either combine this response. Three IFNA2 and IFNA21 chimeras (HY-1, HY-2, different biological properties from the parental proteins or have and HY-3) were constructed using PCR technology and cloned significantly different biological activity from both the parents (3). into a pQE-30 expression vector. The hybrid proteins were ex- Therefore, IFN hybrids have provided a powerful tool for studying pressed in Escherichia coli. These chimeras were selected based the structure-function relationship of these molecules. The engi- on the 1) amino acid sequences of IFN-a2c and IFN-a21a, 2) the neered IFN-a proteins may have important new therapeutic appli- biological activities and binding properties of these IFN-as, and 3) cations and may provide greater insights into understanding of the information derived from the three-dimensional structures of hu- clinical activities of existing IFN-as. man IFN-a consensus and human IFN-b (15, 16). The three-di- mensional model of a human IFN-a consensus sequence reveals *Division of Cytokine Biology, Office of Therapeutics Research and Review, and that the two domains 29–35 and 123–140 are in close spatial prox- †Division of Viral Products, Office of Vaccines Research and Review, Center for imity and may constitute a receptor recognition domain. In con- Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD trast, the residues 78–95 are distant from this region on the mol- 20892 ecule and may influence species specificity and differential Received for publication December 7, 1999. Accepted for publication April 26, 1999. biological activities of the human IFN-as and IFN-b (14). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance The human IFN hybrid proteins were purified using nickel-ni- with 18 U.S.C. Section 1734 solely to indicate this fact. trilotriacetic acid. Agarose and mAb affinity chromatography. The 1 The sequences presented in this article have been submitted to GenBank under antiviral, antiproliferative, binding, signal transduction, and RNase accession numbers HY-1 AF085803, HY-2 AF085804, and HY-3 AF085805. protection properties of the IFN-a hybrids were analyzed and com- 2 Address correspondence and reprint requests to Dr. Renqui Hu, Center for Biologics pared. Our data suggest that a portion of the N-terminal region of Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rock- ville, MD 20892. E-mail address: [email protected] the molecule is important for interaction with receptor compo- a 3 Abbreviations used in this paper: MDBK, Madin-Darby bovine kidney; GRR, g nents, while the C-terminal region of IFN- is critical for antipro- response region; ISRE, IFN-stimulated response element. liferative activity. The EMSA and RNase protection assays of the Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 855 hybrid IFN-as suggest that the antiproliferative response may not Expression and purification be directed by STAT1 and 2 activation alone in either a nonhe- IFNA2, IFNA21, and hybrids HY-2, HY-3 plasmid DNAs were individ- matopoietic cell line, a hematopoietic cell line, or in a primary ually transformed into E. coli strain SG13009[pREP4] (Qiagen), and HY-1 human cell type. plasmid DNA was transformed into E. coli strain DH5aF’IQ (Life Tech- nologies, Gaithersburg, MD). Bacteria were grown in Luria-Bertani broth containing 100 mg/ml ampicillin (HY-1) or 100 mg/ml ampicillin and 25 Materials and Methods mg/ml kanamycin (HY-2, HY-3, IFNA2, and IFNA21) in a 37°C shaker IFN and radiolabeled IFN-a2b incubator overnight. The cultures were diluted 1:50 in Luria-Bertani broth containing the appropriate antibiotic(s) and incubated at 37°C with shaking a Recombinant human IFN- 2b (obtained from Schering, Kenilworth, NJ) to an A600 of 0.8–0.9. Protein expression was induced by 2 mM isopropyl- 8 has an antiviral sp. act. of 2 3 10 IU/mg protein. IFN-a2c (cDNA was 1-thio-b-D-galactopyranoside. The bacteria were then incubated at 30°C cloned into the vector pBluescript; Stratagene, La Jolla, CA) and IFN-a21a for 4–5 h, after which cells were harvested and sonicated. The cell lysate (cDNA from Genentech, South San Francisco, CA) proteins were ex- was clarified by centrifugation at 10,000 3 g for 30 min at 40°C. IFN pressed and purified from E. coli strains transformed with pQE30 as de- purification was performed by nickel-nitrilotriacetic acid. Agarose resin scribed below. IFN-a2b was labeled with 125I-Bolton-Hunter reagent (Am- metal-affinity chromatography (20, 21) and 4F2 mAb affinity chromatog- ersham, Arlington Heights, IL) as previously described (13). raphy (12). The mAb 4F2 recognizes amino acid residues 113–149 of IFN-a consensus (Dr. Bruce Altrock, unpublished observations). Cell and cell culture Protein determination Human Daudi cells were obtained from Dr.
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