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Human and Murine IL-16 Conservation of Structure And Conservation of Structure and Function Between Human and Murine IL-16 Joseph Keane, John Nicoll, Sue Kim, David M. H. Wu, William W. Cruikshank, William Brazer, Barbara Natke, Yujun Zhang, This information is current as David M. Center and Hardy Kornfeld of September 30, 2021. J Immunol 1998; 160:5945-5954; ; http://www.jimmunol.org/content/160/12/5945 Downloaded from References This article cites 42 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/160/12/5945.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 30, 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Conservation of Structure and Function Between Human and Murine IL-161,2 Joseph Keane,3 John Nicoll,3 Sue Kim, David M. H. Wu, William W. Cruikshank,4 William Brazer, Barbara Natke, Yujun Zhang, David M. Center, and Hardy Kornfeld5 IL-16 is a proinflammatory cytokine that signals via CD4, inducing chemotactic and immunomodulatory responses of CD41 lymphocytes, monocytes, and eosinophils. Comparative analysis of murine and human IL-16 homologs could reveal conserved structures that would help to identify key functional regions of these cytokines. To that end, we cloned the murine IL-16 cDNA and found a high degree of amino acid similarity comparing the predicted murine and human IL-16 precursor proteins (pro- IL-16). The highest similarity (82.1%) was found in the C-terminal region, which is cleaved from pro-IL-16 to yield biologically active IL-16. Chemotaxis experiments with IL-16 of murine and human origin, using murine splenocytes or human T lymphocytes Downloaded from as targets, showed cross-species stimulation of motility. Synthetic oligopeptides and anti-peptide Ab were produced, based on the sequences of three predicted hydrophilic domains of IL-16 potentially presented in exposed positions. None of these peptides had intrinsic IL-16 bioactivity, but one (corresponding to a hydrophilic C-terminal domain of IL-16) partially displaced binding of OKT4 mAb to human lymphocytes. This peptide, and its cognate Ab, also inhibited IL-16 chemoattractant activity for human and murine cells. These studies demonstrate a high degree of structural and functional similarity between human and murine IL-16 and suggest that amino acids in the C terminus are critical for its chemoattractant function. The data suggest cross-species http://www.jimmunol.org/ conservation of IL-16 receptor structures as well. Inhibitory peptides may be useful in disease states where the proinflammatory functions of IL-16 are detrimental to the host. The Journal of Immunology, 1998, 160: 5945–5954. n 1982, Cruikshank and Center first reported the functional identify any conserved features that might provide insight to its and biochemical characterization of lymphocyte chemoat- structure and function. Our results indicate a high degree of se- I tractant factor (1, 2), which has more recently been renamed quence similarity and cross-species biologic activity and provide IL-16 (3, 4). Numerous studies have provided evidence that CD4 evidence that the C terminus of IL-16 is required for CD4-medi- serves as a receptor for IL-16 and that IL-16-induced signal trans- ated functions and binding. 1 duction through CD4 induces a variety of responses in CD4 cells, by guest on September 30, 2021 including G0 to G1a cell cycle shift; up-regulation of IL-2R and Materials and Methods HLA-DR expression; transient inhibition of TCR signal transduc- Cell preparations tion and mixed lymphocyte reactions; and repression of HIV-1 Mouse splenocytes were isolated from euthanized BALB/c mice and main- promoter activity (5). tained in RPMI 1640 medium (BioWhittaker, Walkersville, MD) supple- Analysis of human IL-16 cDNA clones indicates that the IL-16 mented with 10% FBS and 100 U/ml of both penicillin and streptomycin mRNA encodes a precursor protein (pro-IL-16), from which a C- (complete medium). Erythrocytes were lysed by suspension in one part complete medium to three parts Gey’s solution. This mixture was incu- terminal biologically active peptide is processed and secreted (6, bated on ice for 2 min. The reaction was stopped by the addition of 10 parts 7). Although the biologic activities of IL-16 have been studied in complete medium, and the cells were washed twice in complete medium some detail, little is known about possible functional domains before use in experiments. Human PBMC were isolated as described from within the secreted molecule. It is also unknown whether there are the blood of healthy normal volunteers by density centrifugation on Ficoll- important functional domains within the precursor protein. In the Paque (1, 2). Samples were enriched for T lymphocytes by nylon wool nonadherence (8). The nonadherent cells were .95% T lymphocytes by current studies, we isolated murine IL-16 cDNA from spleen and flow cytometry. lung and prepared recombinant and natural murine IL-16 protein to IL-16 cDNA clones IL-16 cDNA, 59 to the previously reported 2150 bp (6), was generated by 6 The Pulmonary Center, Boston University School of Medicine, Boston, MA 02118 rapid amplification of 59 ends (RACE), using human T lymphocyte total RNA as the starting material (9). RNA was reverse transcribed using 10 Received for publication August 28, 1997. Accepted for publication February pmol of IL-16-specific primers based on sequences within the 59 region of 12, 1998. the 2150 bp cDNA. The resulting cDNA was tailed with dATP in the The costs of publication of this article were defrayed in part by the payment of page presence of terminal transferase (Life Technologies, Gaithersburg, MD). charges. This article must therefore be hereby marked advertisement in accordance PCR was performed with this cDNA template, using anchored dT17 as the with 18 U.S.C. Section 1734 solely to indicate this fact. 59 primer and IL-16-specific sequences for 39 primers. The DNA sequence 1 Supported by National Institutes of Health Grant HL32802. of PCR products was analyzed on an ABI 373A Genetic Analyzer (Applied 2 The sequences reported in this paper have been deposited into the GenBank database Biosystems, Foster City, CA). Murine IL-16 cDNA clones were isolated (accession nos. AF006001 and M90391). from two cDNA libraries obtained from a commercial vendor (Clontech Laboratories, Palo Alto, CA). One library was generated from mRNA of 3 J.K. and J.N. made equal contributions to the work reported in this manuscript. Their names are listed in alphabetical order. NFS (The Jackson Laboratory, Bar Harbor, ME) mouse splenocytes that had been activated for 12 h with phorbol ester and calcium ionophore. The 4 W.W.C. is a Career Investigator of the American Lung Association. cDNA was produced by oligo(dT) priming, and the cloning vector was 5 Address correspondence and reprint requests to Dr. Hardy Kornfeld, Pulmonary Center, R-3, Boston University School of Medicine, 80 East Concord Street, Boston, MA 02118. 6 Abbreviation used in this paper: RACE, rapid amplification of cDNA ends. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 5946 MURINE IL-16 bacteriophage lgt10. The other cDNA library was prepared from BALB/c Western blot analysis mouse lung using both oligo(dT) and random priming, and the cloning m vector was also bacteriophage lgt10. Both libraries were screened by Affinity-purified native murine IL-16 (40 g) and recombinant IL-16 were plaque hybridization using 32P-labeled probes prepared by nick translation applied to SDS/15% polyacrylamide gels, then transferred to nitrocellulose by electroblotting (3500 Vh, 4°C). The nitrocellulose was incubated2hin of the 2150-bp human IL-16 cDNA (Promega, Madison, WI). One clone 125 was isolated from 105 plaques of the spleen library but was found to be PBS with 1% lactalbumin and 0.05% Tween 20, then probed with I- m incompletely extended 59. A partially overlapping cDNA clone was iso- conjugated polyclonal anti-human rIL-16 Ab added at 1 g/ml for 1 h. lated from the lung library, providing additional 59 sequence information. After washing in PBS, the dried blots were and visualized by autoradiog- Human and murine IL-16 cDNA sequences were analyzed using Lasergene raphy overnight at room temperature. software packages (DNASTAR, Madison, WI) for predicted amino acid Immunoprecipitation sequence similarity by the method of Lipman and Pearson (10), hydrophi- licity profiles by the method of Kyte and Doolittle (11), and surface prob- Anti-IL-16 Abs were incubated with rIL-16 protein at 4°C for 4 h under ability by the method of Emini (12). Potential coding regions were assessed gentle rotation. Protein A-Sepharose beads were added, and the mixture by Fickett’s testcode (13) in the Wisconsin Package Version 9.0 (Genetics incubated for an additional 1 h. The beads were washed three times with Computer Group, Madison, WI). PBS, then resuspended in SDS-PAGE sample buffer and boiled. Released material was analyzed on a 15% SDS-polyacrylamide gel. After electro- Recombinant human and murine IL-16 phoresis, proteins were transferred to nitrocellulose membrane for immu- Recombinant human IL-16 was produced in Escherichia coli as a polyhis- noblotting analysis.
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