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Issue published June 15, 2001 Previous issue | Next issue

  • Volume 107, Issue 12
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  • In this issue
  • Perspectives
  • Commentaries
  • Research Articles
In this issue
In This Issue
John Ashkenas
John Ashkenas
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1479-1479. https://doi.org/10.1172/JCI119928.
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In This Issue

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Abstract

Authors

John Ashkenas

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Perspectives
Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways
Charles N. Serhan, Ernst Oliw
Charles N. Serhan, Ernst Oliw
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1481-1489. https://doi.org/10.1172/JCI13375.
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Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways

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Authors

Charles N. Serhan, Ernst Oliw

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Why there are two cyclooxygenase isozymes
William L. Smith, Robert Langenbach
William L. Smith, Robert Langenbach
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1491-1495. https://doi.org/10.1172/JCI13271.
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Why there are two cyclooxygenase isozymes

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Authors

William L. Smith, Robert Langenbach

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Commentaries
Acute graft-versus-host disease: inflammation run amok?
Joseph H. Antin
Joseph H. Antin
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1497-1498. https://doi.org/10.1172/JCI13259.
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Acute graft-versus-host disease: inflammation run amok?

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Authors

Joseph H. Antin

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Integrin-associated protein (CD47): an unusual activator of G protein signaling
Eric Brown
Eric Brown
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1499-1500. https://doi.org/10.1172/JCI13315.
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Integrin-associated protein (CD47): an unusual activator of G protein signaling

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Authors

Eric Brown

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Pulmonary fibrosis: a cellular overreaction or a failure of communication?
Dean Sheppard
Dean Sheppard
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1501-1502. https://doi.org/10.1172/JCI13318.
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Pulmonary fibrosis: a cellular overreaction or a failure of communication?

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Authors

Dean Sheppard

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ADP and platelets: the end of the beginning
Donna Woulfe, … , Jing Yang, Lawrence Brass
Donna Woulfe, … , Jing Yang, Lawrence Brass
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1503-1505. https://doi.org/10.1172/JCI13361.
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ADP and platelets: the end of the beginning

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Authors

Donna Woulfe, Jing Yang, Lawrence Brass

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TNF and receptors in organ-specific autoimmune disease: multi-layered functioning mirrored in animal models
George Kassiotis, George Kollias
George Kassiotis, George Kollias
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1507-1508. https://doi.org/10.1172/JCI13362.
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TNF and receptors in organ-specific autoimmune disease: multi-layered functioning mirrored in animal models

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Authors

George Kassiotis, George Kollias

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Research Articles
FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation
Michael J. Farrell, … , Tony L. Creazzo, Margaret L. Kirby
Michael J. Farrell, … , Tony L. Creazzo, Margaret L. Kirby
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1509-1517. https://doi.org/10.1172/JCI9317.
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FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation

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Cardiac neural crest ablation results in depressed myocardial calcium transients and elevated proliferation in myocardium at a stage when cardiac neural crest cells are not in contact with the myocardium. To test the hypothesis that cardiac neural crest–derived cells, which migrate into the caudal, ventral pharynx at stage 14, block a signal from the ventral pharynx, we cultured stage 12 chick heart tube or myocardial strips in the presence or absence of ventral pharynx. We found that myocardium cultured with ventral pharynx that had not yet contacted neural crest cells had significantly reduced calcium transients and an increased rate of proliferation. Ventral pharynx from intact embryos at a stage when neural crest–derived cells had reached the pharynx had no effect on myocardial calcium transients. Ventral pharynx from neural crest–ablated embryos continued to suppress myocardial calcium transients at this later stage. Myocardium cultured with FGF-2 also showed a significant reduction in calcium transients. An FGF-2–neutralizing Ab reversed the deleterious effect of the ventral pharynx on myocardial calcium transients and proliferation. We therefore examined the expression of FGF-2 and similar FGFs in the ventral pharynx. Only FGF-8 was expressed in a temporospatial pattern that made it a viable candidate for altering the myocardial calcium transient during stages 14–18. In explant cultures, neutralizing Ab for FGF-8 rescued development of the myocardial calcium transient in neural crest–ablated chick embryos.

Authors

Michael J. Farrell, Jarrett L. Burch, Kathleen Wallis, Linda Rowley, Donna Kumiski, Harriet Stadt, Robert E. Godt, Tony L. Creazzo, Margaret L. Kirby

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Severe inflammatory arthritis and lymphadenopathy in the absence of TNF
Ian K. Campbell, … , Kate E. Lawlor, Ian P. Wicks
Ian K. Campbell, … , Kate E. Lawlor, Ian P. Wicks
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1519-1527. https://doi.org/10.1172/JCI12724.
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Severe inflammatory arthritis and lymphadenopathy in the absence of TNF

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It has been postulated that TNF has a pivotal role in a cytokine cascade that results in joint inflammation and destruction in rheumatoid arthritis (RA). To evaluate this, we examined the response of TNF-deficient (Tnf–/–) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by injection of chick type II collagen (CII) in CFA. Tnf–/– mice had some reduction in the clinical parameters of CIA and, on histology, significantly more normal joints. However, severe disease was evident in 54% of arthritic Tnf–/– joints. Tnf–/– mice had impaired Ig class switching, but preserved T cell proliferative responses to CII and enhanced IFN-γ production. Interestingly, CII-immunized Tnf–/– mice developed lymphadenopathy and splenomegaly associated with increased memory CD4+ T cells and activated lymph node B cells. Acute inflammatory arthritis was also reduced in Tnf–/– mice, although again some mice exhibited severe disease. We conclude that TNF is important but not essential for inflammatory arthritis; in each model, severe arthritis could proceed even in the complete absence of TNF. These results call into doubt the concept that TNF is obligatory for chronic autoimmune and acute inflammatory arthritis and provide a rationale for further studies into TNF-independent cytokine pathways in arthritis.

Authors

Ian K. Campbell, Kristy O’Donnell, Kate E. Lawlor, Ian P. Wicks

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Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis
Martin Kolb, … , Fernando Pitossi, Jack Gauldie
Martin Kolb, … , Fernando Pitossi, Jack Gauldie
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1529-1536. https://doi.org/10.1172/JCI12568.
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Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis

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IL-1β is one of a family of proinflammatory cytokines thought to be involved in many acute and chronic diseases. Although it is considered to participate in wound repair, no major role has been attributed to IL-1β in tissue fibrosis. We used adenoviral gene transfer to transiently overexpress IL-1β in rat lungs after intratracheal administration. The high expression of IL-1β in the first week after injection was accompanied by local increase of the proinflammatory cytokines IL-6 and TNF-α and a vigorous acute inflammatory tissue response with evidence of tissue injury. The profibrotic cytokines PDGF and TGF-β1 were increased in lung fluid samples 1 week after peak expression of IL-1β. Although PDGF returned to baseline in the third week, TGF-β1 showed increased concentrations in bronchoalveolar lavage fluid for up to 60 days. This was associated with severe progressive tissue fibrosis in the lung, as shown by the presence of myofibroblasts, fibroblast foci, and significant extracellular accumulations of collagen and fibronectin. These data directly demonstrate how acute tissue injury in the lung, initiated by a highly proinflammatory cytokine, IL-1β, converts to progressive fibrotic changes. IL-1β should be considered a valid target for therapeutic intervention in diseases associated with fibrosis and tissue remodeling.

Authors

Martin Kolb, Peter J. Margetts, Daniel C. Anthony, Fernando Pitossi, Jack Gauldie

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TGF-β is a critical mediator of acute lung injury
Jean-Francois Pittet, … , Michael A. Matthay, Dean Sheppard
Jean-Francois Pittet, … , Michael A. Matthay, Dean Sheppard
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1537-1544. https://doi.org/10.1172/JCI11963.
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TGF-β is a critical mediator of acute lung injury

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We have shown that the integrin αvβ6 activates latent TGF-β in the lungs and skin. We show here that mice lacking this integrin are completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury (ALI). Pharmacologic inhibition of TGF-β also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. TGF-β directly increased alveolar epithelial permeability in vitro by a mechanism that involved depletion of intracellular glutathione. These data suggest that integrin-mediated local activation of TGF-β is critical to the development of pulmonary edema in ALI and that blocking TGF-β or its activation could be effective treatments for this currently untreatable disorder.

Authors

Jean-Francois Pittet, Mark J.D. Griffiths, Tom Geiser, Naftali Kaminski, Stephen L. Dalton, Xiaozhu Huang, Lou Anne S. Brown, Phillip J. Gotwals, Victor E. Koteliansky, Michael A. Matthay, Dean Sheppard

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Iron overload diminishes atherosclerosis in apoE-deficient mice
Elizabeth A. Kirk, … , Jay W. Heinecke, Renée C. LeBoeuf
Elizabeth A. Kirk, … , Jay W. Heinecke, Renée C. LeBoeuf
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1545-1553. https://doi.org/10.1172/JCI7664.
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Iron overload diminishes atherosclerosis in apoE-deficient mice

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It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE–/–) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE–/– mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo.

Authors

Elizabeth A. Kirk, Jay W. Heinecke, Renée C. LeBoeuf

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Activation of sickle red blood cell adhesion via integrin-associated protein/CD47–induced signal transduction
Julia E. Brittain, … , Eugene P. Orringer, Leslie V. Parise
Julia E. Brittain, … , Eugene P. Orringer, Leslie V. Parise
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1555-1562. https://doi.org/10.1172/JCI10817.
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Activation of sickle red blood cell adhesion via integrin-associated protein/CD47–induced signal transduction

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Peripheral human red blood cells (RBCs) are not generally known to become activated and adhesive in response to cell signaling. We show, however, that soluble thrombospondin via integrin-associated protein (IAP; CD47) increases the adhesiveness of sickle RBCs (SS RBCs) by activating signal transduction in the SS RBC. This stimulated adhesion requires occupancy of IAP and shear stress and is mediated by the activation of large G proteins and tyrosine kinases. Reticulocyte-enriched RBCs derived from sickle-cell disease (SCD) patients are most responsive to IAP-induced activation. These studies therefore establish peripheral SS RBCs as signaling cells that respond to a novel synergy between IAP-induced signal transduction and shear stress, suggesting new therapeutic targets in SCD.

Authors

Julia E. Brittain, Kathryn J. Mlinar, Christopher S. Anderson, Eugene P. Orringer, Leslie V. Parise

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Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis
Kamel Laghmani, … , Masashi Yanagisawa, Robert J. Alpern
Kamel Laghmani, … , Masashi Yanagisawa, Robert J. Alpern
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1563-1569. https://doi.org/10.1172/JCI11234.
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Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis

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Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ETB) receptor increases NHE3 activity. To examine the role of the ETB receptor in the response to acidosis in vivo, the present studies examined ETB receptor–deficient mice, rescued from neonatal lethality by expression of a dopamine β-hydroxylase promoter/ETB receptor transgene (Tg/Tg:ETB–/– mice). In proximal tubule suspensions from Tg/Tg:ETB+/– mice, 10–8 M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ETB–/– mice. Acid ingestion for 7 days caused a greater decrease in blood HCO3– concentration in Tg/Tg:ETB–/– mice compared with Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice. Whereas acid ingestion increased apical membrane NHE3 by 42–46% in Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice, it had no effect on NHE3 in Tg/Tg:ETB–/– mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ETB–/– mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ETB–/– and Tg/Tg:ETB+/+ mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ETB receptor.

Authors

Kamel Laghmani, Patricia A. Preisig, Orson W. Moe, Masashi Yanagisawa, Robert J. Alpern

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Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth
Malcolm J. Low, … , Yogesh C. Patel, Marcelo Rubinstein
Malcolm J. Low, … , Yogesh C. Patel, Marcelo Rubinstein
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1571-1580. https://doi.org/10.1172/JCI11941.
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Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

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Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst–/–) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst–/– compared with Smst+/+ mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst–/– mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst-/- mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth.

Authors

Malcolm J. Low, Veronica Otero-Corchon, Albert F. Parlow, Jose L. Ramirez, Ujendra Kumar, Yogesh C. Patel, Marcelo Rubinstein

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LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
Kenneth R. Cooke, … , Daniel P. Rossignol, James L.M. Ferrara
Kenneth R. Cooke, … , Daniel P. Rossignol, James L.M. Ferrara
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1581-1589. https://doi.org/10.1172/JCI12156.
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LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation

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Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-α levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.

Authors

Kenneth R. Cooke, Armin Gerbitz, James M. Crawford, Takanori Teshima, Geoffrey R. Hill, Amy Tesolin, Daniel P. Rossignol, James L.M. Ferrara

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Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs
Carolyn J. Foster, … , Sergio A. Lira, Madhu S. Chintala
Carolyn J. Foster, … , Sergio A. Lira, Madhu S. Chintala
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1591-1598. https://doi.org/10.1172/JCI12242.
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Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs

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ADP plays a critical role in modulating thrombosis and hemostasis. ADP initiates platelet aggregation by simultaneous activation of two G protein–coupled receptors, P2Y1 and P2Y12. Activation of P2Y1 activates phospholipase C and triggers shape change, while P2Y12 couples to Gi to reduce adenylyl cyclase activity. P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel. Recently, we cloned a human orphan receptor, SP1999, highly expressed in brain and platelets, which responded to ADP and had a pharmacological profile similar to that of P2Y12. To determine whether SP1999 is P2Y12, we generated SP1999-null mice. These mice appear normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen. These platelets retain normal shape change and calcium flux in response to ADP but fail to inhibit adenylyl cyclase. In addition, oral clopidogrel does not inhibit aggregation responses to ADP in these mice. These results demonstrate that SP1999 is indeed the elusive receptor, P2Y12. Identification of the target receptor of the thienopyridine drugs affords us a better understanding of platelet function and provides tools that may lead to the discovery of more effective antithrombotic therapies.

Authors

Carolyn J. Foster, Dina M. Prosser, Jacqueline M. Agans, Ying Zhai, Michelle D. Smith, Jean E. Lachowicz, Fang L. Zhang, Eric Gustafson, Frederick J. Monsma Jr., Maria T. Wiekowski, Susan J. Abbondanzo, Donald N. Cook, Marvin L. Bayne, Sergio A. Lira, Madhu S. Chintala

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A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation
Laurent Coscoy, Don Ganem
Laurent Coscoy, Don Ganem
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1599-1606. https://doi.org/10.1172/JCI12432.
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A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation

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Kaposi’s sarcoma–associated (KS-associated) herpesvirus (KSHV) is a B-lymphotropic agent linked to AIDS-related lymphoproliferative disorders and KS. We and others have earlier identified two viral genes, K3 and K5, that encode endoplasmic reticulum proteins that downregulate surface MHC-I chains by enhancing their endocytosis. Here we have examined the ability of these proteins to influence the disposition of other host surface proteins implicated in immune recognition and activation. We report that K5, but not K3, expression in BJAB cells dramatically reduces ICAM-1 and B7-2 surface expression; B7-1 expression is unaffected. This K5-induced reduction can be reversed by coexpression of a dominant negative mutant of dynamin, indicating that the loss of ICAM and B7-2 surface expression is due to their enhanced endocytosis. This downregulation is functionally significant, because K5-transfected B cells show substantial impairment in their ability to induce T cell activation. K5 is thus the first example of a viral modulator of immunological synapse formation and T cell costimulation. We propose that its expression reduces T cell responses to KSHV-infected B cells early in infection, thereby diminishing antiviral cytokine release and the production of stimulatory signals for CTL generation.

Authors

Laurent Coscoy, Don Ganem

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