DOCSLIB.ORG

Paracrine-Induced Response State Antiviral-Activated Dendritic Cells: A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Paracrine-Induced Response State Antiviral-Activated Dendritic Cells: A Antiviral-Activated Dendritic Cells: A Paracrine-Induced Response State Antonio V. Bordería, Boris M. Hartmann, Ana Fernandez-Sesma, Thomas M. Moran and Stuart C. Sealfon This information is current as of September 24, 2021. J Immunol 2008; 181:6872-6881; ; doi: 10.4049/jimmunol.181.10.6872 http://www.jimmunol.org/content/181/10/6872 Downloaded from References This article cites 53 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/181/10/6872.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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antiviral-Activated Dendritic Cells: A Paracrine-Induced Response State1 Antonio V. Bordería,2* Boris M. Hartmann,2† Ana Fernandez-Sesma,* Thomas M. Moran,* and Stuart C. Sealfon3†‡ Infection of immature dendritic cells (DCs) by virus stimulates their maturation into APC. Infected DCs can also expose uninfected DCs to a panoply of cytokines/chemokines via paracrine signaling. Mathematical modeling suggests that a high rate of paracrine signaling is likely to occur among DCs located in three-dimensional space. Relatively little is known about how secreted factors modify the early response to virus infection. We used a transwell experimental system that allows passage of secreted factors, but not direct contact, between virus-infected DCs and uninfected DCs to investigate paracrine signaling responses. Paracrine signaling from infected DCs induced an antiviral-primed DC state distinct from that of mature virus-infected DCs that we refer to as antiviral-activated DCs (AVDCs). AVDCs had increased surface MHC class II and CD86 levels, but in contrast to virus-infected DCs, their MHC class I levels Downloaded from were unchanged. Imaging flow cytometry showed that AVDCs had an increased rate of phagocytosis compared with naive DCs. Experiments with IFN-␤ cytokine indicated that it may be responsible for CD86, but not MHC class II regulation in AVDCs. Both IFN-inducible and IFN-independent genes are up-regulated in AVDCs. Notably, AVDCs are relatively resistant to virus infection in comparison to naive DCs and achieve accelerated and augmented levels of costimulatory molecule expression with virus infection. AVDCs show a distinct antiviral-primed state of DC maturation mediated by DC paracrine signaling. Although further in vivo study is needed, the characteristics of the AVDC suggest that it is well suited to play a role in the early innate-adaptive transition of the immune http://www.jimmunol.org/ system. The Journal of Immunology, 2008, 181: 6872–6881. endritic cells (DCs)4 are recognized as a key bridge be- TLR-independent intracellular viral product detectors such as RIG-I tween the innate and adaptive immune responses (1). A (8) and/or MDA5 (9, 10). Virus recognition activates a signaling cas- D key event in the development of adaptive immunity cade involving different cellular factors (IFN regulatory factor 3, NF- upon exposure to infection is the maturation of DCs into APCs that ␬B, c-jun), causing the expression of type I IFNs and other inflam- instruct lymphocytes to generate responses to specific Ags. Acti- matory response genes including TNF-␣ and IL-6. The first type I IFN vated DCs efficiently stimulate both innate immune cells, includ- to be produced and secreted is IFN-␤ (11), which signals either in an by guest on September 24, 2021 ing NK cells (2) and NKT cells (3) as well as key components of autocrine or paracrine manner through the IFN receptor (IFNAR) and adaptive immunity including naive (4) and memory (5) B cells and activates the JAK-STAT pathway (12). This signaling cascade further T cells (1). Thus, DCs are important both for innate immunity as amplifies the initial response and creates an antiviral state in adjacent well as for various elements of adaptive immunity (6). cells that renders them resistant to infection. Our study focuses on DC activation by virus infection, using New- Maturation is a complex process, which includes changes in castle disease virus (NDV), a RNA paramyxovirus that has been dem- morphology, loss of endocytic/phagocytic receptors, up-regulation onstrated to be a good model for immune activation (7). DC matura- of costimulatory molecules, such as CD86, translocation of MHC tion is stimulated by detection of various pathogen-associated compartments to the surface, and secretion of cytokines and che- molecular patterns (1) that are characteristic of bacteria, fungi, proto- mokines (13) that attract, differentiate, and polarize other immune zoa, or viruses. DCs recognize virus infection either by TLRs or by effector cells (6). Secretion of chemokines occurs in coordinated waves according to the type of immune cells that need to be at- *Department of Microbiology, †Department of Neurology, and ‡Center for Transla- tracted and activated (13). One late component associated with tional Systems Biology, Mount Sinai School of Medicine, New York, NY maturation is the migration of the DCs to the secondary lymphoid Received for publication April 2, 2008. Accepted for publication September 5, 2008. organs (14), where they interact with the naive T and B cells. This The costs of publication of this article were defrayed in part by the payment of page activation of Ag-specific T cells by mature DCs is a major aspect charges. This article must therefore be hereby marked advertisement in accordance of the initiation of adaptive immunity. with 18 U.S.C. Section 1734 solely to indicate this fact. The secretion of the different cytokines and chemokines affects 1 This work was supported by Contract HHSN266200500021C and Grant U19 AI06231 from the National Institute of Allergy and Infectious Diseases. other immune cells, including immature DCs, by paracrine signal- ing. Consequently, some DCs might be exposed to both cytokines 2 A.V.B. and B.M.H. contributed equally to this work. and microbial products (11), whereas others only to inflammatory 3 Address correspondence and reprint requests to Stuart C. Sealfon, Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of cytokines. Autocrine signaling is regarded as an important mech- Medicine, 1 Gustave L. Levy Place, New York, NY 10029. E-mail address: anism for virus- triggered DC maturation. Integrodifferential mod- [email protected] eling of IFN trajectories suggests that ϳ3% of IFN-␤ interacts 4 Abbreviations used in this paper: DC, dendritic cell; NDV, Newcastle disease virus; with the DCs that produce it (15). AVDC, antiviral-activated DC; MHC-I/II, MHC class I/II; Ct, crossing threshold; DiO, benzoxazolium, 3-octadecyl-2-[3-(3-octadecyl-2(3H)-benzoxazolylidene)-1-propenyl] We investigated the effects of paracrine signaling by DCs on the perchlorate; IP-10, IFN-␥-inducible protein 10; RFP, red fluorescent protein; PKR, pro- response state of DCs that are not infected by virus using NDV, tein kinase R; OAS, 2Ј-5Ј-oligoadenylate synthetase; MxA, myxovirus resistance A. which is detected primarily through the cytosolic RIG-I molecule Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 (16). To study paracrine effects, we used a Transwell system which www.jimmunol.org The Journal of Immunology 6873 is composed of two chambers separated by a membrane that allows soluble components such as cytokines and chemokines to diffuse between chambers, but prohibits direct contact be- tween the cells placed in different chambers. DCs infected with NDV and naive noninfected DCs were placed in the upper and lower chamber, respectively. The culture was left for 18 h, al- lowing the infected DCs to initiate cytokine and chemokine secretion. We found that the naive DCs exposed to the specific cytokine/chemokine secretions released by infected DCs enter a partially activated state in which they are relatively resistant to FIGURE 1. virus infection and primed to generate a more rapid and en- Experimental setup for the generation of AVDCs. hanced response to virus infection. compartment to mimic the condition during AVDC generation. We incu- Materials and Methods bated cells for 18 h at 37°C. Naive DCs in the lower compartment were Differentiation of DCs then stained for the maturation markers MHC class I (MHC-I), MHC class All human research protocols for this work have been reviewed and ap- II (MHC-II), and CD86. proved by the Institutional Review Board of the Mount Sinai School of Culture of human lung fibroblast Medicine. Monocyte-derived DCs were obtained from healthy human blood donors following a standard protocol described elsewhere (7). All Lung epithelial fibroblasts were obtained from Lonza and cultured accord- Downloaded from experiments were replicated using cells obtained from different donors. ing to the supplier’s instructions. Briefly, cells were passed when conflu- Briefly, human PBMC were isolated from buffy coats by Ficoll density ence was 70–80% using fibroblast basal medium supplemented with hu- gradient centrifugation (Histopaque; Sigma-Aldrich) at 1450 rpm and man fibroblast growth factor ␤, insulin, FBS, and gentamicin/amphotericin ϩ CD14 monocytes were immunomagnetically purified by using a B. To perform experiments in the Transwell system, 3 ϫ 105 cells were MACS CD14 isolation kit (Miltenyi Biotec).
Load more

Recommended publications
  • Paracrine and Autocrine Functions of PDGF in Malignant Disease
    ! " #$ %&#'( )*#+& (%( ,'-./'%(%' (+'.,' (+( 00 Paracrine and autocrine functions of PDGF in malignant disease BY TOBIAS SJÖBLOM Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Molecular Cell Biology presented at Uppsala University in 2002. ABSTRACT Sjöblom T. 2002. Paracrine and autocrine functions of PDGF in malignant disease. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1190. 62pp. Uppsala. ISBN 91-554-5420-8. Growth factors and their receptors are frequently activated by mutations in human cancer. Platelet-derived growth factor (PDGF)-B and its tyrosine kinase receptor, the PDGF β- receptor, have been implicated in autocrine transformation as well as paracrine stimulation of tumor growth. The availability of clinically useful antagonists motivates evaluation of PDGF inhibition in these diseases. In chronic myelomonocytic leukemia with t(5;12), parts of the transcription factor TEL and the PDGF β-receptor are fused, generating a constitutively signaling protein. Oligomerization and unique phosphorylation pattern of TEL-PDGFβR was demonstrated, as well as the transforming activity of TEL-PDGFβR, which was sensitive to PDGF β-receptor kinase inhibition. Dermatofibrosarcoma protuberans (DFSP) is characterized by a translocation involving the collagen Iα1 and PDGF B-chain genes. The COLIA1-PDGFB fusion protein was processed to mature PDGF-BB and transformed fibroblasts in culture. The PDGF antagonist STI571 inhibited growth of COLIA1-PDGFB transfected cells and primary DFSP cells in vitro and in vivo through induction of apoptosis. Paracrine effects of PDGF-DD, a ligand for the PDGF β-receptor, were evaluated in a murine model of malignant melanoma. PDGF-DD production accelerated tumor growth and altered the vascular morphology in experimental melanomas.
    [Show full text]
  • Met Receptor Tyrosine Kinase: Enhanced Signaling Through Adapter Proteins
    Oncogene (2000) 19, 5582 ± 5589 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Met receptor tyrosine kinase: enhanced signaling through adapter proteins Kyle A Furge1, Yu-Wen Zhang1 and George F Vande Woude*,1 1Van Andel Research Institute, 333 Bostwick, N.E., Grand Rapids, Michigan, MI 49503, USA The Met receptor tyrosine kinase is the prototypic matrix (`invasion') (Jeers et al., 1996c; Matsumoto et member of a small subfamily of growth factor receptors al., 1994; Rong et al., 1994; Weidner et al., 1990). In that when activated induce mitogenic, motogenic, and addition, HGF/SF-Met signaling can induce several morphogenic cellular responses. The ligand for Met is dierent epithelial and mesenchymal cell types to hepatocyte growth factor/scatter factor (HGF/SF) and undergo an involved dierentiation program termed while normal HGF/SF-Met signaling is required for branching morphogenesis when the cells are grown in a embryonic development, abnormal Met signaling has three dimensional matrix (Brinkmann et al., 1995; been strongly implicated in tumorigenesis, particularly in Jeers et al., 1996c; Montesano et al., 1991a; Niemann the development of invasive and metastatic phenotypes. et al., 1998). During branching morphogenesis, groups Following ligand binding and autophosphorylation, Met of cells proliferate, migrate, and dierentiate to form a transmits intercellular signals using a unique multi- connected series of tubules arranged like branches from substrate docking site present within the C-terminal a tree. However, even in the absense of a three end of the receptor. The multisubstrate docking site dimensional matrix, signaling through the Met receptor mediates the binding of several adapter proteins such as can induce morphogenesis and lumen formation in Grb2, SHC, Crk/CRKL, and the large adapter protein certain cell types (Jeers et al., 1996a; Tsarfaty et al., Gab1.
    [Show full text]
  • Paracrine Wnt1 Drives Interstitial Fibrosis Without Inflammation by Tubulointerstitial Cross-Talk
    BASIC RESEARCH www.jasn.org Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk † Omar H. Maarouf,* Anusha Aravamudhan,* Deepika Rangarajan,* Tetsuro Kusaba,* ‡ Victor Zhang,* Jeremy Welborn,* Daniel Gauvin,* Xiuyun Hou,* Rafael Kramann,* and † Benjamin D. Humphreys* § *Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; †Harvard Medical School, Boston, Massachusetts; ‡Division of Nephrology and Clinical Immunology and Medical Faculty, Rheinisch- Westfälische Technische Hochschule Aachen University, Aachen, Germany; and §Harvard Stem Cell Institute, Cambridge, Massachusetts ABSTRACT AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury–induced epithelial secretion of profibrotic factors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast acti- vation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFb– dependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared
    [Show full text]
  • Network Analysis Reveals Abberant Cell Signaling In
    NETWORK ANALYSIS REVEALS ABBERANT CELL SIGNALING IN MURINE DIABETIC KIDNEY By PRIYANKA GOPAL Submitted in partial fulfillment of the requirements Master of Science Thesis Advisor: Michael Simonson PhD Department of Physiology and Biophysics CASE WESTERN RESERVE UNIVERSITY May, 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Priyanka Gopal Candidate for the degree of Master of Science Committee Chair Dr. William P. Schilling, PhD Committee Member Dr. Christopher P. Ford, PhD Committee Member Dr. Jeffrey L. Garvin, PhD Committee Member Dr. Michael S. Simonson, PhD Date of Defense 03/16/2015 *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents………………………………………………………………………...iii List of Tables……………………………………………………………………………..iv List of Figures…………………………………………………………………………….v Acknowledgements………………………………………………………………………vi List of Abbreviations…………………………………………………………………....vii Abstract…………………………………………………………………..........................x Introduction…………….……………………………………………...............................1 Research Objectives and Specific Aims………………………………………………….5 Materials and Methods……………………………………………………………………6 Results……………………………………………………………………………………11 Discussion………………………………………………………………………………..16 Summary and Future Directions…………………………………………………………21 Bibliography……………………………………………………………………………..37 iii List of Tables Table 1 Quantitative PCR measurements of mRNA for putative first messengers altered in 16 week
    [Show full text]
  • Paracrine Signaling Mediated at Cellcell Contacts
    Insights & Perspectives Think again Paracrine signaling mediated at cellÀcell contacts Sougata Roy*,† and Thomas B. Kornberg Recent findings in several organ systems show that cytoneme-mediated systems. However, recent work that we signaling transports signaling proteins along cellular extensions and targets discuss here describes paracrine signal- cell-to-cell exchanges to synaptic contacts. This mechanism of paracrine ing that is instead contact-mediated and signaling may be a general one that is used by many (or all) cell types in many (or dependent on transient synapses that all) organs. We briefly review these findings in this perspective. We also non-neuronal cells make. These synap- describe the properties of several signaling systems that have previously been ses form at sites where specialized signaling filopodia called cytonemes interpreted to support a passive diffusion mechanism of signaling protein extend to contact target cells. dispersion, but can now be understood in the context of the cytoneme mechanism. Keywords: The classical model of .cytonemes; filopodia; morphogen; paracrine signaling; synapse; TGF-b paracrine signaling assumes that signals disperse by passive Introduction so that signals are within only 15À20 nm diffusion of their target receptors when they are Animal cells communicate over long released. Paracrine signaling, the third There are many paracrine signaling distances in various ways. Endocrine general mechanism, may be considered proteins that have been characterized. cells signal systemically by releasing to be a variant of endocrine signaling, They include the Fibroblast Growth hormones that disseminate in the vas- functioning at relatively short range Factors (FGFs) and other proteins that culature. Neurons also release signals, when secreted signals move limited activate Receptor Tyrosine Kinases, but they exchange information at syn- distances by passive diffusion in extra- TGF-b family members, Wnt proteins, apses that form where their axons and cellular fluid.
    [Show full text]
  • Cell Communication and Signaling Mechanisms Terms to Learn
    LQB383 Testbank Week 8 – Cell Communication and Signaling Mechanisms Terms to learn – match the terms to the definitions -------------------------------------------------------------------------------------------------------------------------- Adaptor Intracellular signaling protein Morphogen Endocrine cell Gap junction Neurotransmitter Hormone Receptor Extracellular signal molecule Signaling cascade Steroid hormone Synaptic signaling Paracrine signaling Second messenger Autocrine signaling Nuclear receptor family Interaction domain Contact-dependent signaling Definitions 1. General term for a protein that binds a specific extracellular molecule (ligand) and initiates a response in a cell. 2. Communicating cell-cell junction that allows ions and small molecules to pass from the cytoplasm of one cell to the cytoplasm of another. 3. Hydrophobic signaling molecule with characteristic four-ringed structure derived from cholesterol. 4. Short-range cell-cell communication via secreted local mediators that act on adjacent cells. 5. Specialised cell that secretes a hormone into the blood 6. The cell responds to its own secreted molecules. 7. Small signaling molecule secreted by the presynaptic nerve cell at a chemical synapse to relay the signal to the postsynaptic cell. 8. Small molecule that is formed in the cytosol, or released into it, in response to an extracellular signal, and that helps to relay the signal in the interior of the cell. 9. Molecule from the outside of the cell that communicates the behaviour or actions of other cells in the environment and elicits an appropriate response. 10. General term for a signal relay chain containing multiple amplification steps. 1 Receptor 2 Gap junction 3 Steroid hormone 4 Paracrine signaling 5 Endocrine cell 6 Autocrine signaling 7 Neurotransmitter 8 Second messenger 9 Extracellular signal molecule 10 Signaling cascade Multiple Choice Questions 1.
    [Show full text]
  • Paracrine Signaling by Progesterone ⇑ Renuga Devi Rajaram, Cathrin Brisken
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Infoscience - École polytechnique fédérale de Lausanne Molecular and Cellular Endocrinology xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Review Paracrine signaling by progesterone ⇑ Renuga Devi Rajaram, Cathrin Brisken Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC – Swiss Institute for Experimental Cancer Research, NCCR Molecular Oncology, SV2832 Station 19, CH-1015 Lausanne, Switzerland article info abstract Article history: Steroid hormones coordinate and control the development and function of many organs and are impli- Available online xxxx cated in many pathological processes. Progesterone signaling, in particular, is essential for several impor- tant female reproductive functions. Physiological effects of progesterone are mediated by its cognate Keywords: receptor, expressed in a subset of cells in target tissues. Experimental evidence has accumulated that pro- Progesterone receptor gesterone acts through both cell intrinsic as well as paracrine signaling mechanisms. By relegating the Paracrine signaling hormonal stimulus to paracrine signaling cascades the systemic signal gets amplified locally and signal- Uterus ing reaches different cell types that are devoid of hormone receptors. Interestingly, distinct biological Ovaries responses to progesterone in different target tissues rely on several tissue-specific and some common Mammary gland Carcinogenesis paracrine factors that coordinate biological responses in different cell types. Evidence is forthcoming that the intercellular signaling pathways that control development and physiological functions are important in tumorigenesis. Crown Copyright Ó 2011 Published by Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . ....................................................................................................... 00 2.
    [Show full text]
  • CD44 and Integrin Matrix Receptors Participate in Cartilage Homeostasis
    CMLS, Cell. Mol. Life Sci. 59 (2002) 36–44 1420-682X/02/010036-09 $ 1.50 + 0.20/0 © Birkhäuser Verlag, Basel, 2002 CMLS Cellular and Molecular Life Sciences CD44 and integrin matrix receptors participate in cartilage homeostasis W. Knudson a, * and R. F. Loeser a, b a Department of Biochemistry, Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois 60612 (USA), Fax +1 312 942 3053, e-mail: [email protected] b Section of Rheumatology, Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois 60612 (USA) Abstract. Articular chondrocytes express the matrix re- to detect changes in matrix composition or to function as ceptors CD44 and integrins. Both of these receptors ex- mechanotransducers. Disruption of CD44 or integrin- hibit interactions with adjacent extracellular matrix mediated cell-matrix interactions, either experimentally macromolecules. In addition, both integrins and CD44 induced or when present in osteoarthritis, have profound have the capacity for signal transduction as well as mod- effects on cartilage metabolism. Thus, CD44 and integrin ulated interactions with the actin cytoskeleton. As such, receptors play a critical role in maintaining cartilage both receptor families provide the chondrocytes a means homeostasis. Key words. CD44; hyaluronan; proteoglycan; integrin; collagen; fibronectin; chondrocyte. In many tissues, carefully regulated cell-matrix interac- drocytes, CD44 represents the primary receptor responsi- tions are responsible for maintaining tissue homeostasis ble for hyaluronan (HA) binding [4, 9]. However, in carti- [1–4]. Most cell-matrix interactions are mediated via lage, HA is seldom present as a pure molecule. Often more transmembrane receptors. Articular chondrocytes have than 50 aggrecan proteoglycan (PG) monomers together been shown to express both integrin [5–7]) as well as with an associated link protein become bound to a single nonintegrin (e.g., annexin V and CD44) extracellular ma- filament of HA [13].
    [Show full text]
  • Differential Expression of Cytokines and Receptor Expression During
    Plotkin et al. BMC Res Notes (2018) 11:406 https://doi.org/10.1186/s13104-018-3520-5 BMC Research Notes RESEARCH NOTE Open Access Diferential expression of cytokines and receptor expression during anoxic growth Balbina J. Plotkin* , Ira M. Sigar, Julie A. Swartzendruber, Amber Kaminski and James Davis Abstract Objective: Cell density in tumor cell three dimensional (3D) cultures afects secretome expression of components. A microenvironment characteristic shared by high-density 3D cell culture and in vivo tumor masses is poor oxygena- tion, with anoxia being a natural cell state in tumor centers. Until recently, the ability to study anoxia-adapted cell physiology was not possible. Using a newly-developed methodology, anoxic HeLa cell secretome expression was measured. Results: Anoxic HeLa cell cytokine levels after 3 days’ (hypoxia inducible factor, HIF1 positive) and 10 days’ growth (HIF1 negative; anaerobic respiration) were signifcantly (p < 0.01) higher than normoxic controls for: IL-8 (1.8- and 3.4- fold higher, respectively), GRO (1.3- and 1.1-fold higher, respectively), and IL-11 (1.4- and 1.1-fold higher, respectively). In contrast, G-CSF, IFNα2, and CXCL-10 levels decreased over time (day 3 vs. day 10). Thus, metabolically active HeLa cells respond to the lack of oxygen, in part, by regulating the levels of cytokines produced. Cytokines expressed at increased levels, in the absence of oxygen, correspond to a secretomic profle reported for paracrine signaling path- ways associated with metastasis. Further studies defning physiologic changes that occur upon anoxic growth may lead to the discovery of novel chemotherapeutic drug targets.
    [Show full text]
  • Dual Inhibition of PI3K and Mtor Inhibits Autocrine and Paracrine Proliferative Loops in PI3K/Akt/Mtor-Addicted Lymphomas
    LYMPHOID NEOPLASIA Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas *Aadra P. Bhatt,1 *Prasanna M. Bhende,1 Sang-Hoon Sin,1 Debasmita Roy,1 Dirk P. Dittmer,1 and Blossom Damania1 1Lineberger Comprehensive Cancer Center and Department of Microbiology & Immunology, University of North Carolina at Chapel Hill Primary effusion lymphoma (PEL) consti- rely heavily on PI3K/Akt/mTOR signaling, and in a PEL xenograft tumor model. NVP- tutes a subset of non-Hodgkin lymphoma are dependent on autocrine and paracrine BEZ235 was effective at low nanomolar con- whose incidence is highly increased in growth factors, and also have a poor progno- centrations and has oral bioavailability. We the context of HIV infection. Kaposi sarcoma– sis with reported median survival times of also report a novel mechanism for NVP- associated herpesvirus is the causative less than 6 months. We compared different BEZ235 involving the suppression of mul- agent of PEL. The phosphatidylinositol compounds that inhibit the PI3K/Akt/mTOR tiple autocrine and paracrine growth factors 3-kinase (PI3K) signaling pathway plays a pathway in PEL. Although compounds that required for lymphoma survival. Our data critical role in cell proliferation and survival, modulated activity of only a single pathway have broad applicability for the treatment of and this pathway is dysregulated in many member inhibited PEL proliferation, the use cytokine-dependent tumors with PI3K/mTOR different cancers, including PEL, which dis- of a novel compound, NVP-BEZ235, that dual inhibitors. (Blood. 2010;115(22): play activated PI3K, Akt, and mammalian dually inhibits both PI3K and mTOR kinases 4455-4463) target of rapamycin (mTOR) kinases.
    [Show full text]
  • Network Dynamics Determine the Autocrine and Paracrine Signaling Functions of TNF
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Network dynamics determine the autocrine and paracrine signaling functions of TNF Andrew B. Caldwell,1,4 Zhang Cheng,1,2,3 Jesse D. Vargas,1,2,3 Harry A. Birnbaum,1,2,3 and Alexander Hoffmann1,2,3 1Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA; 2Institute for Quantitative and Computational Biosciences, 3Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90025, USA A hallmark of the inflammatory response to pathogen exposure is the production of tumor necrosis factor (TNF) that coordinates innate and adaptive immune responses by functioning in an autocrine or paracrine manner. Numerous molecular mechanisms contributing to TNF production have been identified, but how they function together in macrophages remains unclear. Here, we pursued an iterative systems biology approach to develop a quantitative understanding of the regulatory modules that control TNF mRNA synthesis and processing, mRNA half-life and translation, and protein processing and secretion. By linking the resulting model of TNF production to models of the TLR-, the TNFR-, and the NFkB signaling modules, we were able to study TNF’s functions during the inflammatory response to diverse TLR agonists. Contrary to expectation, we predicted and then experimentally confirmed that in response to lipopolysaccaride, TNF does not have an autocrine function in amplifying the NFkB response, although it plays a potent paracrine role in neighboring cells.
    [Show full text]
  • Hedgehog Signaling: Networking to Nurture a Promalignant Tumor Microenvironment
    Published OnlineFirst July 20, 2011; DOI: 10.1158/1541-7786.MCR-11-0175 Molecular Cancer Subject Review Research Hedgehog Signaling: Networking to Nurture a Promalignant Tumor Microenvironment Lillianne G. Harris, Rajeev S. Samant, and Lalita A. Shevde Abstract In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors. Mol Cancer Res; 9(9); 1165–74.
    [Show full text]