DOCSLIB.ORG

US7572600.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
US7572600.Pdf US007572600B2 (12) United States Patent (10) Patent No.: US 7,572,600 B2 Berahovich et al. (45) Date of Patent: Aug. 11, 2009 (54) ENZYMATIC ACTIVITIES IN WO WO90, 13332 11, 1990 CHEMOKNE-MEDIATED INFLAMMATION WO WO 91/12779 9, 1991 WO WO 91f17271 11, 1991 (75) WO WO91, 1898O 12/1991 Inventors: Robert D. Berahovich, Berkeley, CA WO WO92fO1047 1, 1992 (US); Zhenhua Miao, San Jose, CA WO WO93,06121 4f1993 (US); Brett Premack, San Francisco, WO WO93, 17706 9, 1993 CA (US); Thomas J. Schall, Palo Alto, WO WO93/24640 12/1993 CA (US) WO WO94,08051 4f1994 WO WO94/20142 9, 1994 (73) Assignee: Chemocentryx, Inc., Mt. View, CA (US) WO WO95/12608 5, 1995 WO WO95/30642 11, 1995 (*) Notice: Subject to any disclaimer, the term of this WO WO95/35503 12/1995 patent is extended or adjusted under 35 WO WO 98.04554 2, 1998 U.S.C. 154(b) by 486 days. OTHER PUBLICATIONS (21) Appl. No.: 11/198,935 Al-Obeidi (1998), Mol. Biotechnol. 9:205-223. Aoyama, Y. et al. (2001), Bioorg Med. Chem. Lett. 11: 1691-4. (22) Filed: Aug. 4, 2005 Amour, A., et al. (1998), J. Pharm. Pharmacol. 50:593-600. Berger, M.S. etal (1993), DNA Cell Biol 12:839-847. (65) Prior Publication Data Bao, L., et al. (1992), Genomics 13:437-40. US 2006/OO63223 A1 Mar. 23, 2006 Berman et al. (1988), Immunol. Invest. 17: 625-677. Baici, A. (1993), Biochem. Pharmacol. 46:1545-9. Bae, Y.-S. et al. (2004) J Immunol. 173:607-614. Related U.S. Application Data Beusen, D. (1995), Biopolymers 36:181-200. (60) Provisional application No. 60/598.959, filed on Aug. Banerjee, A. (1996), Biopolymers 39:769-777. 4, 2004. Berkhout, T.A. et al. (2000), Biochem Pharmacol 59:591-6. Coligan (1991), Current Protocols. In Immunology, Wiley/Greene, Int. C. NY. (51) Cooley, J. (2001), Biochemistry 40: 15762-70. CI2O I/00 (2006.01) Christopherson, K.W., II, et al (2002), J Immunol 169:7000-7008. CI2O I/37 (2006.01) Crump, M.P. et al (1997), EMBOJ 16:6996-7007. (52) U.S. Cl. ........................................................ 435/23 Cui, P. et al. (2001), J Leukoc Biol 70:306–312. (58) Field of Classification Search ..................... 435/4, Chertov, O. et al. (1997), J Exp Med 186:739-747. 435/23 Durstin, M., et al. (1994), Biochem Biophy's Res Commun 201:174-9. See application file for complete search history. Dole and Nelson (1999), J. Combinatorial Chemistry 1:235-282. Delgado, M.B. etal (2001), Eur.J Immunol 31:699-707. (56) References Cited Ehrlich et al. (1980), Biochem 19:4091-4096. U.S. PATENT DOCUMENTS Escher, S.E., et al. (2004), J. Pept. Res.63:36-47. Goding (1986), Monoclonal Antibodies. Principles And Practice (2d 4,458,066 A 7, 1984 Caruthers et al. ed.), Academic Press, New York, NY. 4,733,655 A 3, 1988 Smal Graham et al. (1977), J. Gen. Virol. 36:59-72. 4,800,882 A 1, 1989 Gianturco Gitschow, M. et al. (2002), Arch. Biochem. Biophy's. 402:180-191. 4,816,567 A 3/1989 Cabilly et al. Gilman et al. (1941), (Eds) Organic Syntheses Collective Volumes, 4,886,062 A 12, 1989 Wiktor John Wiley & Sons, Inc., NY. 5,124.350 A 6/1992 Djuric et al. Grimshaw, M.J. et al. (2002), Eur.J Immunol 32:2393-2400. 5,284,746 A 2f1994 Sledziewski et al. Hayashi, Y. et al. (2000), Bioorg. Med. Chem. Lett. 10:199-201. 5,419,760 A 5/1995 Narciso, Jr. 5,422,426 A 6, 1995 DiMarchi et al. (Continued) 5,429,634 A 7/1995 Narciso, Jr. 5,530,101 A 6/1996 Queen et al. Primary Examiner Jon P Weber 5,545,806 A 8/1996 Longberg et al. Assistant Examiner Kailash C Srivastava 5,563,762 A 10/1996 Leung et al. (74) Attorney, Agent, or Firm—Brinks Hofer Gilson & Lione 5,569,825 A 10/1996 Longberg et al. 5,585,089 A 12/1996 Queen et al. (57) ABSTRACT 5,693,761 A 12/1997 Queen et al. 5,693,762 A 12/1997 Queen et al. 5,736,524 A 4, 1998 Content et al. Truncated chemokines lacking an N-terminal region that acti 6,329,510 B1* 12/2001 Qin et al. ............... 530,38822 vate CCR1 and/or FPRL1 and compositions containing the 6,723,538 B2 * 4/2004 Macket al. ................ 435/69.7 truncated chemokines are provided. Methods of identifying 6,756,035 B2 6/2004 Qin et al. agents that modulate CCR1 and/or FPRL1 activity either by 6,770,729 B2 8/2004 Van Antwerp modulating the production of the truncated chemokines or the 2003/0096.260 A1* 5/2003 Miao et al. ..................... 435/6 ability of the truncated chemokines to activate CCR1 and/or 2004/0243225 A1 12/2004 Ragheb et al. FPRL1 are also disclosed. Methods using the truncated chemokines to inhibit or activate CCR1 and/or FPRL1 medi FOREIGN PATENT DOCUMENTS ated biological activities are also disclosed. GB 2276.169 9, 1994 WO WO90, 11092 10, 1990 10 Claims, 25 Drawing Sheets US 7,572,600 B2 Page 2 OTHER PUBLICATIONS Poltorak, A.N. et al. (1995), J Inflamm 45:207-219. Queen, et al. (1989), Proc. Nat'l Acad. Sci. USA 86: 10029-10033. Huse et al. (1989), Science 246:1275-81. Rajarathnam, K. etal (2001), J Biol Chem 276:4909-4916. Hogg, P.J., et al. (1993), J. Biol. Chem. 268:21811-8. Raymond, W.W. et al. (2003), J. Biol. Chem. 278:34517-34524. He, S. et al. (1997), J Immunol 159:6216-6225. Rehault, S. (1999), J. Biol. Chem. 274: 13810-13817. Hara, T. et al. (1995), J Immunol 155:53.52-5358. Rand, M. et al. (1996), Am. J. Pathol. 148:855-864. Hogaboam, C.M. et al. (1999), J Immunol 162:6071-6079. Ransohoff, R.M. et al. (1996), Cytokine Growth Factor Rev. 7:35-46. Janusz, M.J. and Hare, M. (1994), Int. J. Immunopharmacol. 16:623 Springer-Verlag, N.Y., (1994), Protein Purification. Principles And 32. Practice (3' Edition). Kavanaugh et al. (1991), J. Immunol. 146:4149-4156. Shinguh, Y. et al. (1997), Eur: J. Pharmacol. 337:63-71. Korkmaz, B. et al. (2004), Am. J. Respir: Cell Mol. Biol. 30:801-807. Sabroe, I., et al. (2000), J. Biol. Chem. 275:25985-25992. Kohler, G. and Milstein, A. (1975), Nature 256:495-97. Spatola (1983), Chemistry and Biochemistry of Amino Acids, Kettleborough, C.A. et al. (1991), Protein Engineering 4:773-783. Peptides and Proteins, vol. 7, pp. 267-357, Peptide Backbone Modi Kuang, R. etal (2000), Bioorg. Med. Chem. 8:1005-1016. fications, Marcell Dekker, NY. Levy, B.D. et al. (2002), Nat Med 8:1018-23. Smith, A.B. (1992), J. Amer: Chem. Soc. 114: 10672-10674. Langer, R. (1990), Science 249:1527-1533. Struyf, S. etal (1998), Eur.J Immunol 28:1262-1271. Ludwig, A. etal (2002), J Leukoc Biol 72: 183-191. Shimizu, T. et al. (2002), Arthritis Rheum 46:2330-2338. Macphee, C. H. et al. (1998), J. Immunol. 161:6273-6279. Tomimori, Y. et al. (2002), Biochem Pharmacol 64: 1187. McBride J.D., et al. (1999), Eur: J. Biochem. 266:403-412. Tani, K. et al. (2000), Am J Respir Crit Care Med 161: 1636-1642. Masaki, H., et al. (2003), Bioorg. Med Chem. Lett. 13:4085-8. Ulmer, J. et al. (1993), Science 259:1745-1749. McQuibban, G.A. et al. (2000), Science 289:1202-1206. Vicentini, C.B. et al. (2001), J. Enzyme Inhib. 16:15-34. McQuibban, G.A. et al. (2001), J Biol Chem 276:43503-43508. Vagnoni, L.M. et al. (2001), Bioorg. Med. Chem. 9:637-45. McQuibban, G.A. etal (2002), Blood 100: 1160-1167. Wells, A. et al. (1985), Gene 34:315-323. Mohamadzadeh, M. et al. (1996), J Immunol 156:3102-3106. Winnacker, E.L. (1987), From Genes To Clones VCH Publishers, Neote, K. et al. (1993), Cell 72: 415-425. N.Y., N.Y. Nagai, U. (1985), Tet. Lett. 26:647-650. Ward, E.S. et al. (1989), Nature341:544-46. Oravecz, T. et al. (1997), J Exp Med 186:1865-1872. Wieczorek, M. et al. (1999), Arch. Biochem. Biophy's. 367: 193-201. Patel, V.P. et al. (1997), J Exp Med 185: 1163-72. Weg, J.B. et al. (1993), J. Exp. Med. 177:561-566. Proost, P. etal (2001), Blood 98:3554-3561. * cited by examiner U.S. Patent Aug. 11, 2009 Sheet 1 of 25 US 7,572,600 B2 Figure 1A QFINDAETELMMSKLPLENPVVLNSFHFAADCC. CCL15/MP-18 VINSFHFAADCC . -- eastase VLNSFHFAADCC. ... + PMN sup #1 VLNSFHFAADCC. ... + PMN sup #2 SFHFAADCC. ... + synovial AADCC. ... + cathepsin G AADCC. -- chymase Figure 1B s costa cosa cks CCs CCL15thyrise CCL15+ chyrase oc1st PMN split CCS cathepsin-G ocCl5synonial Cis- easts ue PMN sup alone war CCL154 PNNsus 2 syrosiastone PAN2 one a. s 2 s Figure 1C U.S. Patent US 7,572,600 B2 U.S. Patent 000; 0 t g a r N re (s sun 03uoso on) nauts unbrea U.S. Patent Aug. 11, 2009 Sheet 6 of 25 US 7,572,600 B2 (9L:ON (LI:ON (8L:ON (6T:ON (ÜZ:ON {IZ:ON (6:ON (£I:ON (GI:ONCII (OI:ONCII (II:ONQI (ZT:ONCII CII CII CII QI CII QI ÕES) SI?9InáH U.S. Patent Aug. 11, 2009 Sheet 7 Of 25 US 7,572,600 B2 U.S. Patent Aug. 11, 2009 Sheet 8 of 25 US 7,572,600 B2 rycznoo þzyoSZTOO e.
Load more

Recommended publications
  • Mouse CD163 Deficiency Strongly Enhances Experimental Collagen-Induced Arthritis
    www.nature.com/scientificreports OPEN Mouse CD163 defciency strongly enhances experimental collagen‑induced arthritis Pia Svendsen1,2, Anders Etzerodt 3, Bent W. Deleuran3,4 & Søren K. Moestrup1,2,5* The scavenger receptor CD163 is highly expressed in macrophages in sites of chronic infammation where it has a not yet defned role. Here we have investigated development of collagen‑induced arthritis (CIA) and collagen antibody‑induced arthritis (CAIA) in CD163‑defcient C57BL/6 mice. Compared to wild‑type mice, the CIA in CD163‑defcient mice had a several‑fold higher arthritis score with early onset, prolonged disease and strongly enhanced progression. Further, the serum anti‑ collagen antibody isotypes as well as the cytokine profles and T cell markers in the infamed joints revealed that CD163‑defcient mice after 52 days had a predominant Th2 response in opposition to a predominant Th1 response in CD163+/+ mice. Less diference in disease severity between the CD163+/+ and CD163−/− mice was seen in the CAIA model that to a large extent induces arthritis independently of T‑cell response and endogenous Th1/Th2 balance. In conclusion, the present set of data points on a novel strong anti‑infammatory role of CD163. Te scavenger receptor CD163 is expressed exclusively in cells of monocytic origin with a high expression in M2-type macrophages where it has an established role in scavenging hemoglobin (Hb) released into plasma 1. Te receptor and its function have been most intensively studied in human systems, but the selective myelomonocytic expression of CD163 with a high upregulation in the M2-type macrophages is also seen in animals including rodents2,3.
    [Show full text]
  • Responses During Sepsis Interactions Exacerbate Innate Immune CCR1
    The Journal of Immunology CCR1 and CC Chemokine Ligand 5 Interactions Exacerbate Innate Immune Responses during Sepsis1 Traci L. Ness,* Kristin J. Carpenter,* Jillian L. Ewing,* Craig J. Gerard,† Cory M. Hogaboam,2* and Steven L. Kunkel* CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1؊/؊) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1؊/؊ mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leu- -kocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1؊/؊ resident or recruited peri toneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1؊/؊ mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-␥ and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention. The Journal of Immunology, 2004, 173: 6938–6948. epsis is the most common cause of death in noncoronary mune response to sepsis (7, 8).
    [Show full text]
  • Retinoid X Receptor Α Controls Innate Inflammatory Responses Through The
    Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression Vanessa Núñeza,1, Daniel Alamedaa,1, Daniel Ricoa,2, Rubén Motab, Pilar Gonzalob, Marta Cedenillaa, Thierry Fischerc, Lisardo Boscád, Christopher K. Glasse, Alicia G. Arroyob, and Mercedes Ricotea,3 Departments of aRegenerative Cardiology and bVascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain; cDepartment of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid 28049, Spain; dInstituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid 28029, Spain; and eDepartment of Medicine, Department of Cellular and Molecular Medicine, University of California, La Jolla, CA 92093 Edited* by Daniel Steinberg, University of California, La Jolla, CA, and approved April 19, 2010 (received for review November 25, 2009) The retinoid X receptor α (RXRα) plays a central role in the regulation Chemokines and their receptors have been implicated in the of many intracellular receptor signaling pathways and can mediate modulation of leukocyte trafficking, immune/inflammatory respon- ligand-dependent transcription by forming homodimers or hetero- ses, sepsis, and multiorgan failure (18, 19). Clinical studies have also dimers with other nuclear receptors. Although several members of identified elevated levels of chemokines associated with human the nuclear hormone receptor superfamily have emerged as impor- sepsis and acute lung injury (20). tant regulators of macrophage gene expression, the existence in vivo We have examined the role of RXRα in the innate immune of an RXR signaling pathway in macrophages has not been estab- system by conditionally disrupting RXRα in myeloid cells. We lished. Here, we provide evidence that RXRα regulates the transcrip- show that chemokines Ccl6 and Ccl9 are novel target genes for tion of the chemokines Ccl6 and Ccl9 in macrophages independently RXRα in primary peritoneal macrophages.
    [Show full text]
  • CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer's Patch Cd11b+ Dendritic Cells
    CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer's Patch CD11b+ Dendritic Cells This information is current as Xinyan Zhao, Ayuko Sato, Charles S. Dela Cruz, Melissa of October 1, 2021. Linehan, Andreas Luegering, Torsten Kucharzik, Aiko-Konno Shirakawa, Gabriel Marquez, Joshua M. Farber, Ifor Williams and Akiko Iwasaki J Immunol 2003; 171:2797-2803; ; doi: 10.4049/jimmunol.171.6.2797 http://www.jimmunol.org/content/171/6/2797 Downloaded from References This article cites 32 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/171/6/2797.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on October 1, 2021 *average 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 Errata An erratum has been published regarding this article. Please see next page or: /content/172/11/7220.2.full.pdf 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer’s Patch CD11b؉ Dendritic Cells1 Xinyan Zhao,2* Ayuko Sato,* Charles S.
    [Show full text]
  • Myelin-Specific CD8 T Cells Exacerbate Brain Inflammation in CNS Autoimmunity
    Myelin-specific CD8 T cells exacerbate brain inflammation in CNS autoimmunity Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman J Clin Invest. 2019. https://doi.org/10.1172/JCI132531. Research In-Press Preview Autoimmunity Graphical abstract Find the latest version: https://jci.me/132531/pdf Myelin-specific CD8 T cells exacerbate brain inflammation in CNS autoimmunity Catriona A. Wagner1, Pamela J. Roqué1, Trevor R. Mileur1, Denny Liggitt2, and Joan M. Goverman1* 1Departments of Immunology and 2Comparative Medicine, University of Washington, Seattle, WA, USA *Corresponding author: Dr. Joan M. Goverman Department of Immunology, University of Washington Box 358059 750 Republican St, Seattle, WA 98109 Tel: +1 206-685-7604 Fax: +1 206-616-4561 Email: [email protected] The authors declare no competing financial interests. Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4 T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8 T cells in disease pathogenesis. We previously showed that an MHC class I-restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4 T cell-initiated EAE. Here, we investigated whether naïve MBP-specific CD8 T cells recruited to the CNS during CD4 T cell-initiated EAE engaged in determinant-spreading and influenced disease. We found that the MBP-specific CD8 T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I-restricted MBP ligand in the brain compared to the spinal cord.
    [Show full text]
  • Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection
    Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection This information is current as Bennett Davenport, Jens Eberlein, Tom T. Nguyen, of September 24, 2021. Francisco Victorino, Verena van der Heide, Maxim Kuleshov, Avi Ma'ayan, Ross Kedl and Dirk Homann J Immunol published online 18 September 2020 http://www.jimmunol.org/content/early/2020/09/17/jimmun ol.2000254 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/09/17/jimmunol.200025 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 24, 2021 *average 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 18, 2020, doi:10.4049/jimmunol.2000254 The Journal of Immunology Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection Bennett Davenport,*,†,‡,x,{ Jens Eberlein,*,† Tom T. Nguyen,*,‡ Francisco Victorino,*,†,‡ Verena van der Heide,x,{ Maxim Kuleshov,‖,# Avi Ma’ayan,‖,# Ross Kedl,† and Dirk Homann*,†,‡,x,{ Pathogen-specific memory T cells (TM) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning.
    [Show full text]
  • NF-Κb Dependent Chemokine Signaling in Pancreatic Cancer
    cancers Review NF-κB Dependent Chemokine Signaling in Pancreatic Cancer Claudia Geismann 1, Heiner Schäfer 1,2 , Jan-Paul Gundlach 3, Charlotte Hauser 3 , Jan-Hendrik Egberts 3, Günter Schneider 4 and Alexander Arlt 1,* 1 Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] (C.G.); [email protected] (H.S.) 2 Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany 3 Department of Surgery, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] (J.-P.G.); [email protected] (C.H.); [email protected] (J.-H.E.) 4 Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-431-5002-2210 Received: 30 August 2019; Accepted: 24 September 2019; Published: 26 September 2019 Abstract: Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes.
    [Show full text]
  • Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-Out Mouse Models
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Neurobiol Manuscript Author . Author Manuscript manuscript; Author available in PMC 2017 July 01. Published in final edited form as: Mol Neurobiol. 2017 July ; 54(5): 3119–3130. doi:10.1007/s12035-016-9884-4. Inflammation in Lafora Disease: evolution with disease progression in laforin and malin knock-out mouse models Irene López-González, MSc1,#, Rosa Viana, PhD4,#, Pascual Sanz, PhD4,5,CA, and Isidre Ferrer, MD, PhD1,2,3,CA 1Institute of Neuropathology, Bellvitge University Hospital, Idibell, Hospitalet de Llobregat, Barcelona, Spain 2University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain 3CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Ministry of Science and Innovation, Institute Carlos III, Spain 4Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas; Valencia, Spain 5CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Institute Carlos III, Spain Abstract Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a−/− (laforin knock-out) and Epm2b−/− (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences.
    [Show full text]
  • Lineage-Specific Functions of Bcl-6 in Immunity and Inflammation Are Mediated by Distinct Biochemical Mechanisms
    ARTICLES Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms Chuanxin Huang, Katerina Hatzi & Ari Melnick The transcription factor Bcl-6 orchestrates germinal center (GC) reactions through its actions in B cells and T cells and regulates inflammatory signaling in macrophages. Here we found that genetic replacement with mutated Bcl6 encoding Bcl-6 that cannot bind corepressors to its BTB domain resulted in disruption of the formation of GCs and affinity maturation of immunoglobulins due to a defect in the proliferation and survival of B cells. In contrast, loss of function of the BTB domain had no effect on the differentiation and function of follicular helper T cells or that of other helper T cell subsets. Bcl6-null mice had a lethal inflammatory phenotype, whereas mice with a mutant BTB domain had normal healthy lives with no inflammation. The repression of inflammatory responses by Bcl-6 in macrophages was accordingly independent of the repressor function of the BTB domain. Bcl-6 thus mediates its actions through lineage-specific biochemical functions. Bcl-6 is a transcriptional repressor originally identified as being Bcl-6 is a member of the BTB–zinc finger family of proteins. Its BTB encoded by a locus frequently translocated in diffuse large B cell lym- domain forms an obligate homodimer and it contains C2H2 zinc fin- phomas (DLBCLs)1. During normal development, Bcl-6 has critical gers that bind to DNA. The interface between monomers of the Bcl-6 functions in various cell types of the adaptive and innate compart- BTB domain creates two symmetrical extended lateral grooves that ments of the immune system.
    [Show full text]
  • A Novel Role for Constitutively Expressed Epithelial-Derived Chemokines As Antibacterial Peptides in the Intestinal Mucosa
    ARTICLES nature publishing group A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa K K o t a r s k y 1 , K M S i t n i k 1 , H S t e n s t a d 1 , H K o t a r s k y 2 , A S c h m i d t c h e n 3 , M K o s l o w s k i 4 , J We h k a m p 4 a n d W W A g a c e 1 Intestinal-derived chemokines have a central role in orchestrating immune cell influx into the normal and inflamed intestine. Here, we identify the chemokine CCL6 as one of the most abundant chemokines constitutively expressed by both murine small intestinal and colonic epithelial cells. CCL6 protein localized to crypt epithelial cells, was detected in the gut lumen and reached high concentrations at the mucosal surface. Its expression was further enhanced in the small intestine following in vivo administration of LPS or after stimulation of the small intestinal epithelial cell line, mICc12 , with IFN , IL-4 or TNF . Recombinant- and intestinal-derived CCL6 bound to a subset of the intestinal microflora and displayed antibacterial activity. Finally, the human homologs to CCL6, CCL14 and CCL15 were also constitutively expressed at high levels in human intestinal epithelium, were further enhanced in inflammatory bowel disease and displayed similar antibacterial activity. These findings identify a novel role for constitutively expressed, epithelial-derived chemokines as antimicrobial peptides in the intestinal mucosa.
    [Show full text]
  • Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade a C Imran G
    Published OnlineFirst October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade A C Imran G. House1,2, Peter Savas2,3, Junyun Lai1,2, Amanda X.Y. Chen1,2, Amanda J. Oliver1,2, Zhi L. Teo2,3, Kirsten L. Todd1,2, Melissa A. Henderson1,2, Lauren Giuffrida1,2, Emma V. Petley1,2, Kevin Sek1,2, Sherly Mardiana1,2, Tuba N. Gide4, Camelia Quek4, Richard A. Scolyer4,5, Georgina V. Long4,6,7, James S. Wilmott4, Sherene Loi2,3, Phillip K. Darcy1,2,8,9, and Paul A. Beavis1,2 ABSTRACT ◥ Purpose: Response rates to immune checkpoint blockade (ICB; single-cell RNA-sequencing (RNA-seq) and paired survival anti-PD-1/anti-CTLA-4) correlate with the extent of tumor analyses. immune infiltrate, but the mechanisms underlying the recruit- Results: The CXCR3 ligands, CXCL9 and CXCL10, were sig- ment of T cells following therapy are poorly characterized. A nificantly upregulated following dual PD-1/CTLA-4 blockade and þ greater understanding of these processes may see the develop- both CD8 T-cell infiltration and therapeutic efficacy were CXCR3 ment of therapeutic interventions that enhance T-cell recruit- dependent. In both murine models and patients undergoing immu- ment and, consequently, improved patient outcomes. We there- notherapy, macrophages were the predominant source of CXCL9 þ fore investigated the chemokines essential for immune cell and their depletion abrogated CD8 T-cell infiltration and the recruitment and subsequent therapeutic efficacy of these immu- therapeutic efficacy of dual ICB.
    [Show full text]
  • The CCL6 Chemokine Is Differentially Regulated by C-Myc and L-Myc, and Promotes Tumorigenesis and Metastasis1
    [CANCER RESEARCH 63, 2923–2932, June 1, 2003] The CCL6 Chemokine Is Differentially Regulated by c-Myc and L-Myc, and Promotes Tumorigenesis and Metastasis1 Fenghua Yi, Ronald Jaffe, and Edward V. Prochownik2 Section of Hematology/Oncology, Departments of Pediatrics [F. Y., E. V. P.] and Pathology [R. J.], Children’s Hospital of Pittsburgh; The Department of Molecular Genetics and Biochemistry, The University of Pittsburgh Medical Center [E. V. P.]; and the University of Pittsburgh Cancer Institute [E. V. P.], Pittsburgh, Pennsylvania 15213 ABSTRACT A major goal in the study of Myc proteins has been to identify their target genes. A number of these have now been characterized, mostly The CCL6 chemokine gene was identified as a direct positive target of the as a result of the application of DNA microarray technology (6–12). L-Myc oncoprotein in interleukin 3-dependent 32D myeloid cells. A mutant Many of the target genes encode proteins involved in cell cycle form of c-Myc, lacking a region of the NH2-terminal domain necessary for transcriptional repression (c-Myc⌬MBII), also up-regulated CCL6. Chroma- control, DNA synthesis, metabolism, apoptosis, and extracellular ma- tin immunoprecipitation showed that L-Myc, c-Myc⌬MBII, and full-length trix formation. Some are also transforming when overexpressed (5, 6). c-Myc all bound the CCL6 promoter, although the latter was inactive in A related goal that has received little attention concerns the degree transcriptional up-regulation. Exogenously added CCL6 induced marked of overlap among the transcriptional targets for the three MYC genes. apoptosis in some cell types. However, in 32D cells, the coexpression of c-Myc Indirect evidence suggesting that some, if not all, of these targets are and CCL6 abrogated interleukin 3 dependence and produced a highly leu- the same, derives from studies demonstrating that the embryonic kemogenic phenotype.
    [Show full text]