Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Issue published February 15, 2004 Previous issue | Next issue

  • Volume 113, Issue 4
Go to section:
  • In this issue
  • Book Review
  • Science in Medicine
  • News
  • Commentaries
  • Research Articles
  • Corrigendum
In this issue
In This Issue
/articles/view/119993
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):493-493. https://doi.org/10.1172/JCI119993.
View: Text | PDF

In This Issue

  • Text
  • PDF
Abstract

Authors

×
Book Review
A brand-new bird: how two amateur scientists created the first genetically engineered animal
Steve Goldman
Steve Goldman
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):495-495. https://doi.org/10.1172/JCI21127.
View: Text | PDF

A brand-new bird: how two amateur scientists created the first genetically engineered animal

  • Text
  • PDF
Abstract

Authors

Steve Goldman

×
Science in Medicine
Human African trypanosomiasis of the CNS: current issues and challenges
Peter G.E. Kennedy
Peter G.E. Kennedy
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):496-504. https://doi.org/10.1172/JCI21052.
View: Text | PDF

Human African trypanosomiasis of the CNS: current issues and challenges

  • Text
  • PDF
Abstract

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease.

Authors

Peter G.E. Kennedy

×
News
Assessing risk is the business of prion disease research
Laurie Goodman
Laurie Goodman
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):494-494. https://doi.org/10.1172/JCI21128.
View: Text | PDF

Assessing risk is the business of prion disease research

  • Text
  • PDF
Abstract

Authors

Laurie Goodman

×
Commentaries
Into the depths of ataxia
Harry T. Orr
Harry T. Orr
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):505-507. https://doi.org/10.1172/JCI21092.
View: Text | PDF

Into the depths of ataxia

  • Text
  • PDF
Abstract

Ataxia is a lethal neurological disease characterized by incoordination, postural abnormalities, difficulties with gait, and problems with clarity of speech. The etiology of ataxia is divided equally between hereditary and sporadic forms. Regardless of cause, the cerebellar cortex is often a target in ataxia. Thus, how a disruption in cerebellar cortex might lead to ataxia is of considerable interest. A report in this issue of the JCI links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei.

Authors

Harry T. Orr

×

The eosinophil enigma
Timothy J. Williams
Timothy J. Williams
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):507-509. https://doi.org/10.1172/JCI21073.
View: Text | PDF

The eosinophil enigma

  • Text
  • PDF
Abstract

Eosinophils accumulate in high numbers in the lungs of asthmatic patients. These cells have the ability to induce tissue damage, a capacity that relates to their traditional role in host defense against parasitic worms. On the other hand, eosinophils produce growth factors associated with tissue repair and remodeling, notably TGF-β1. The relationship of these activities to lung dysfunction in asthma is highly controversial, but recent observations in humans and in animal models add spice to the debate .

Authors

Timothy J. Williams

×

HDL action on the vascular wall: is the answer NO?
Philip W. Shaul, Chieko Mineo
Philip W. Shaul, Chieko Mineo
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):509-513. https://doi.org/10.1172/JCI21072.
View: Text | PDF

HDL action on the vascular wall: is the answer NO?

  • Text
  • PDF
Abstract

Circulating levels of HDL cholesterol are inversely related to the risk of atherosclerosis, and therapeutic increases in HDL reduce the incidence of cardiovascular events. A new study shows that HDL-associated lysophospholipids stimulate the production of the potent antiatherogenic signaling molecule NO by the vascular endothelium.

Authors

Philip W. Shaul, Chieko Mineo

×

Fighting cancer by disrupting C-terminal methylation of signaling proteins
Steven Clarke, Fuyuhiko Tamanoi
Steven Clarke, Fuyuhiko Tamanoi
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):513-515. https://doi.org/10.1172/JCI21059.
View: Text | PDF

Fighting cancer by disrupting C-terminal methylation of signaling proteins

  • Text
  • PDF
Abstract

Protein methylation at the C-terminus of mammalian isoprenylated proteins has been implicated in membrane attachment, protein-protein interactions, and protein stability. A new paper describes surprising results: in the absence of methylation some target proteins have increased stability, whereas others have decreased stability. The decreased stability of the RhoA protein is correlated with an increased resistance to Ras-dependent transformation and suggests the basis for the development of a new approach to antitumor therapy .

Authors

Steven Clarke, Fuyuhiko Tamanoi

×
Research Articles
Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):516-527. https://doi.org/10.1172/JCI18420.
View: Text | PDF

Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis

  • Text
  • PDF
Abstract

Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.

Authors

Clare R. Ozawa, Andrea Banfi, Nicole L. Glazer, Gavin Thurston, Matthew L. Springer, Peggy E. Kraft, Donald M. McDonald, Helen M. Blau

×

Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease
Iris T. Chan, … , Tyler Jacks, D. Gary Gilliland
Iris T. Chan, … , Tyler Jacks, D. Gary Gilliland
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):528-538. https://doi.org/10.1172/JCI20476.
View: Text | PDF

Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease

  • Text
  • PDF
Abstract

Oncogenic ras alleles are among the most common mutations found in patients with acute myeloid leukemia (AML). Previously, the role of oncogenic ras in cancer was assessed in model systems overexpressing oncogenic ras from heterologous promoters. However, there is increasing evidence that subtle differences in gene dosage and regulation of gene expression from endogenous promoters play critical roles in cancer pathogenesis. We characterized the role of oncogenic K-ras expressed from its endogenous promoter in the hematopoietic system using a conditional allele and IFN-inducible, Cre-mediated recombination. Mice developed a completely penetrant myeloproliferative syndrome characterized by leukocytosis with normal maturation of myeloid lineage cells; myeloid hyperplasia in bone marrow; and extramedullary hematopoiesis in the spleen and liver. Flow cytometry confirmed the myeloproliferative phenotype. Genotypic and Western blot analysis demonstrated Cre-mediated excision and expression, respectively, of the oncogenic K-ras allele. Bone marrow cells formed growth factor–independent colonies in methylcellulose cultures, but the myeloproliferative disease was not transplantable into secondary recipients. Thus, oncogenic K-ras induces a myeloproliferative disorder but not AML, indicating that additional mutations are required for AML development. This model system will be useful for assessing the contribution of cooperating mutations in AML and testing ras inhibitors in vivo.

Authors

Iris T. Chan, Jeffery L. Kutok, Ifor R. Williams, Sarah Cohen, Lauren Kelly, Hirokazu Shigematsu, Leisa Johnson, Koichi Akashi, David A. Tuveson, Tyler Jacks, D. Gary Gilliland

×

Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf
Martin O. Bergo, … , Patrick J. Casey, Stephen G. Young
Martin O. Bergo, … , Patrick J. Casey, Stephen G. Young
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):539-550. https://doi.org/10.1172/JCI18829.
View: Text | PDF

Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf

  • Text
  • PDF
Abstract

Isoprenylcysteine carboxyl methyltransferase (Icmt) methylates the carboxyl-terminal isoprenylcysteine of CAAX proteins (e.g., Ras and Rho proteins). In the case of the Ras proteins, carboxyl methylation is important for targeting of the proteins to the plasma membrane. We hypothesized that a knockout of Icmt would reduce the ability of cells to be transformed by K-Ras. Fibroblasts harboring a floxed Icmt allele and expressing activated K-Ras (K-Ras-Icmtflx/flx) were treated with Cre-adenovirus, producing K-Ras-IcmtΔ/Δ fibroblasts. Inactivation of Icmt inhibited cell growth and K-Ras–induced oncogenic transformation, both in soft agar assays and in a nude mice model. The inactivation of Icmt did not affect growth factor–stimulated phosphorylation of Erk1/2 or Akt1. However, levels of RhoA were greatly reduced as a consequence of accelerated protein turnover. In addition, there was a large Ras/Erk1/2-dependent increase in p21Cip1, which was probably a consequence of the reduced levels of RhoA. Deletion of p21Cip1 restored the ability of K-Ras-IcmtΔ/Δ fibroblasts to grow in soft agar. The effect of inactivating Icmt was not limited to the inhibition of K-Ras–induced transformation: inactivation of Icmt blocked transformation by an oncogenic form of B-Raf (V599E). These studies identify Icmt as a potential target for reducing the growth of K-Ras– and B-Raf–induced malignancies.

Authors

Martin O. Bergo, Bryant J. Gavino, Christine Hong, Anne P. Beigneux, Martin McMahon, Patrick J. Casey, Stephen G. Young

×

Inhibition of airway remodeling in IL-5–deficient mice
Jae Youn Cho, … , Stephanie Friedman, David H. Broide
Jae Youn Cho, … , Stephanie Friedman, David H. Broide
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):551-560. https://doi.org/10.1172/JCI19133.
View: Text | PDF

Inhibition of airway remodeling in IL-5–deficient mice

  • Text
  • PDF
Abstract

To determine the role of IL-5 in airway remodeling, IL-5–deficient and WT mice were sensitized to OVA and challenged by repetitive administration of OVA for 3 months. IL-5–deficient mice had significantly less peribronchial fibrosis (total lung collagen content, peribronchial collagens III and V) and significantly less peribronchial smooth muscle (thickness of peribronchial smooth muscle layer, α-smooth muscle actin immunostaining) compared with WT mice challenged with OVA. WT mice had a significant increase in the number of peribronchial cells staining positive for major basic protein and TGF-β. In contrast, IL-5–deficient mice had a significant reduction in the number of peribronchial cells staining positive for major basic protein, which was paralleled by a similar reduction in the number of cells staining positive for TGF-β, suggesting that eosinophils are a significant source of TGF-β in the remodeled airway. OVA challenge induced significantly higher levels of airway epithelial αVβ6 integrin expression, as well as significantly higher levels of bioactive lung TGF-β in WT compared with IL-5–deficient mice. Increased airway epithelial expression of αVβ6 integrin may contribute to the increased activation of latent TGF-β. These results suggest an important role for IL-5, eosinophils, αVβ6, and TGF-β in airway remodeling.

Authors

Jae Youn Cho, Marina Miller, Kwang Je Baek, Ji Won Han, Jyothi Nayar, Sook Young Lee, Kirsti McElwain, Shauna McElwain, Stephanie Friedman, David H. Broide

×

Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism
Takashi Shimada, … , Kazuma Tomizuka, Takeyoshi Yamashita
Takashi Shimada, … , Kazuma Tomizuka, Takeyoshi Yamashita
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):561-568. https://doi.org/10.1172/JCI19081.
View: Text | PDF

Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

  • Text
  • PDF
Abstract

Inorganic phosphate is essential for ECM mineralization and also as a constituent of important molecules in cellular metabolism. Investigations of several hypophosphatemic diseases indicated that a hormone-like molecule probably regulates serum phosphate concentration. FGF23 has recently been recognized as playing important pathophysiological roles in several hypophosphatemic diseases. We present here the evidence that FGF23 is a physiological regulator of serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) by generating FGF23-null mice. Disruption of the Fgf23 gene did not result in embryonic lethality, although homozygous mice showed severe growth retardation with abnormal bone phenotype and markedly short life span. The Fgf23–/– mice displayed significantly high serum phosphate with increased renal phosphate reabsorption. They also showed an elevation in serum 1,25(OH)2D that was due to the enhanced expression of renal 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase) from 10 days of age. These phenotypes could not be explained by currently known regulators of mineral homeostasis, indicating that FGF23 is essential for normal phosphate and vitamin D metabolism.

Authors

Takashi Shimada, Makoto Kakitani, Yuji Yamazaki, Hisashi Hasegawa, Yasuhiro Takeuchi, Toshiro Fujita, Seiji Fukumoto, Kazuma Tomizuka, Takeyoshi Yamashita

×

HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3
Jerzy-Roch Nofer, … , Jerold Chun, Bodo Levkau
Jerzy-Roch Nofer, … , Jerold Chun, Bodo Levkau
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):569-581. https://doi.org/10.1172/JCI18004.
View: Text | PDF

HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

  • Text
  • PDF
Abstract

HDL is a major atheroprotective factor, but the mechanisms underlying this effect are still obscure. HDL binding to scavenger receptor-BI has been shown to activate eNOS, although the responsible HDL entities and signaling pathways have remained enigmatic. Here we show that HDL stimulates NO release in human endothelial cells and induces vasodilation in isolated aortae via intracellular Ca2+ mobilization and Akt-mediated eNOS phosphorylation. The vasoactive effects of HDL could be mimicked by three lysophospholipids present in HDL: sphingosylphosphorylcholine (SPC), sphingosine-1-phosphate (S1P), and lysosulfatide (LSF). All three elevated intracellular Ca2+ concentration and activated Akt and eNOS, which resulted in NO release and vasodilation. Deficiency of the lysophospholipid receptor S1P3 (also known as LPB3 and EDG3) abolished the vasodilatory effects of SPC, S1P, and LSF and reduced the effect of HDL by approximately 60%. In endothelial cells from S1P3-deficient mice, Akt phosphorylation and Ca2+ increase in response to HDL and lysophospholipids were severely reduced. In vivo, intra-arterial administration of HDL or lysophospholipids lowered mean arterial blood pressure in rats. In conclusion, we identify HDL as a carrier of bioactive lysophospholipids that regulate vascular tone via S1P3-mediated NO release. This mechanism may contribute to the vasoactive effect of HDL and represent a novel aspect of its antiatherogenic function.

Authors

Jerzy-Roch Nofer, Markus van der Giet, Markus Tölle, Iza Wolinska, Karin von Wnuck Lipinski, Hideo A. Baba, Uwe J. Tietge, Axel Gödecke, Isao Ishii, Burkhard Kleuser, Michael Schäfers, Manfred Fobker, Walter Zidek, Gerd Assmann, Jerold Chun, Bodo Levkau

×

Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia
Vikram G. Shakkottai, … , Frank M. LaFerla, K. George Chandy
Vikram G. Shakkottai, … , Frank M. LaFerla, K. George Chandy
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):582-590. https://doi.org/10.1172/JCI20216.
View: Text | PDF

Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

  • Text
  • PDF
Abstract

Cerebellar ataxia, a devastating neurological disease, may be initiated by hyperexcitability of deep cerebellar nuclei (DCN) secondary to loss of inhibitory input from Purkinje neurons that frequently degenerate in this disease. This mechanism predicts that intrinsic DCN hyperexcitability would cause ataxia in the absence of upstream Purkinje degeneration. We report the generation of a transgenic (Tg) model that supports this mechanism of disease initiation. Small-conductance calcium-activated potassium (SK) channels, regulators of firing frequency, were silenced in the CNS of Tg mice with the dominant-inhibitory construct SK3-1B-GFP. Transgene expression was restricted to the DCN within the cerebellum and was detectable beginning on postnatal day 10, concomitant with the onset of cerebellar ataxia. Neurodegeneration was not evident up to the sixth month of age. Recordings from Tg DCN neurons revealed loss of the apamin-sensitive after-hyperpolarization current (IAHP) and increased spontaneous firing through SK channel suppression, indicative of DCN hyperexcitability. Spike duration and other electrogenic conductance were unaffected. Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value. This dominant-inhibitory strategy may help define the in vivo role of SK channels in other neuronal pathways.

Authors

Vikram G. Shakkottai, Chin-hua Chou, Salvatore Oddo, Claudia A. Sailer, Hans-Günther Knaus, George A. Gutman, Michael E. Barish, Frank M. LaFerla, K. George Chandy

×

Vanin-1–/– mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores
Florent Martin, … , Philippe Naquet, Bouchra Gharib
Florent Martin, … , Philippe Naquet, Bouchra Gharib
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):591-597. https://doi.org/10.1172/JCI19557.
View: Text | PDF

Vanin-1–/– mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores

  • Text
  • PDF
Abstract

Vanin-1 is a membrane-anchored pantetheinase highly expressed in the gut and liver. It hydrolyzes pantetheine to pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine. The latter is believed to be a key regulating factor of several essential metabolic pathways, acting through sulfhydryl-disulfide exchange reactions between sulfhydryl groups of the enzymes and the oxidized form, cystamine. Its physiological importance remains to be elucidated, however. To explore this point, we developed Vanin-1–deficient mice that lack free cysteamine. We examined the susceptibility of deficient mice to intestinal inflammation, either acute (NSAID administration) or chronic (Schistosoma infection). We found that Vanin-1–/– mice better controlled inflammatory reaction and intestinal injury in both experiments. This protection was associated with increased γ-glutamylcysteine synthetase activity and increased stores of reduced glutathione, as well as reduced inflammatory cell activation in inflamed tissues. Oral administration of cystamine reversed all aspects of the deficient phenotype. These findings suggest that one cysteamine function is to upregulate inflammation. Consequently, the pantetheinase activity of Vanin-1 molecule could be a target for a new anti-inflammatory strategy.

Authors

Florent Martin, Marie-France Penet, Fabrice Malergue, Hubert Lepidi, Alain Dessein, Franck Galland, Max de Reggi, Philippe Naquet, Bouchra Gharib

×

The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport
Joshua VanHouten, … , Margaret Neville, John J. Wysolmerski
Joshua VanHouten, … , Margaret Neville, John J. Wysolmerski
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):598-608. https://doi.org/10.1172/JCI18776.
View: Text | PDF

The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport

  • Text
  • PDF
Abstract

The transfer of calcium from mother to milk during lactation is poorly understood. In this report, we demonstrate that parathyroid hormone–related protein (PTHrP) production and calcium transport in mammary epithelial cells are regulated by extracellular calcium acting through the calcium-sensing receptor (CaR). The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation. Increasing concentrations of calcium, neomycin, and a calcimimetic compound suppress PTHrP secretion by mammary epithelial cells in vitro, whereas in vivo, systemic hypocalcemia increases PTHrP production, an effect that can be prevented by treatment with a calcimimetic. Hypocalcemia also reduces overall milk production and calcium content, while increasing milk osmolality and protein concentrations. The changes in milk calcium content, milk osmolality, and milk protein concentration were mitigated by calcimimetic infusions. Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP. We conclude that the lactating mammary gland can sense calcium and adjusts its secretion of calcium, PTHrP, and perhaps water in response to changes in extracellular calcium concentration. We believe this defines a homeostatic system that helps to match milk production to the availability of calcium.

Authors

Joshua VanHouten, Pamela Dann, Grace McGeoch, Edward M. Brown, Karen Krapcho, Margaret Neville, John J. Wysolmerski

×

Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation
Devashish Kothapalli, … , Daniel J. Rader, Richard K. Assoian
Devashish Kothapalli, … , Daniel J. Rader, Richard K. Assoian
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):609-618. https://doi.org/10.1172/JCI19097.
View: Text | PDF

Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation

  • Text
  • PDF
Abstract

HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor–binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein–dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. Indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE.

Authors

Devashish Kothapalli, Ilia Fuki, Kamilah Ali, Sheryl A. Stewart, Liang Zhao, Ron Yahil, David Kwiatkowski, Elizabeth A. Hawthorne, Garret A. FitzGerald, Michael C. Phillips, Sissel Lund-Katz, Ellen Puré, Daniel J. Rader, Richard K. Assoian

×

Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells
Daphne C. Tsitoura, Paul B. Rothman
Daphne C. Tsitoura, Paul B. Rothman
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):619-627. https://doi.org/10.1172/JCI18975.
View: Text | PDF

Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells

  • Text
  • PDF
Abstract

Glucocorticoids have potent immunosuppressive properties, but their effects are often modulated by the conditions prevailing in the local immune milieu. In this study we determined whether the action of glucocorticoids is influenced by the degree of signaling during T cell activation. We found that dexamethasone (Dex) effectively suppressed T cell receptor–induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-κB transcriptional activity. However, enhancement of TCR signaling by CD28- or IL-2–mediated costimulation abrogated the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. The amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T cell activation. In particular, costimulatory signaling via MAPK kinase (MEK) and extracellular signal–regulated kinase (ERK) was essential for the development of T cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. In contrast, transmission of IL-2 signals via STAT5 and CD28 signals via NF-κB remained inhibited by Dex. These results imply that the immune system, by regulating the degree of local costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.

Authors

Daphne C. Tsitoura, Paul B. Rothman

×

Mast cell dipeptidyl peptidase I mediates survival from sepsis
Jon Mallen–St. Clair, … , George H. Caughey, Paul J. Wolters
Jon Mallen–St. Clair, … , George H. Caughey, Paul J. Wolters
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):628-634. https://doi.org/10.1172/JCI19062.
View: Text | PDF

Mast cell dipeptidyl peptidase I mediates survival from sepsis

  • Text
  • PDF
Abstract

Sepsis is a common, life-threatening disease for which there is little treatment. The cysteine protease dipeptidyl peptidase I (DPPI) activates granule-associated serine proteases, several of which play important roles in host responses to bacterial infection. To examine DPPI’s role in sepsis, we compared DPPI–/– and DPPI+/+ mice using the cecal ligation and puncture (CLP) model of septic peritonitis, finding that DPPI–/– mice are far more likely to survive sepsis. Outcomes of CLP in mice lacking mast cell DPPI reveal that the absence of DPPI in mast cells, rather than in other cell types, is responsible for the survival advantage. Among several cytokines surveyed in peritoneal fluid and serum, IL-6 is highly and differentially expressed in DPPI–/– mice compared with DPPI+/+ mice. Remarkably, deleting IL-6 expression in DPPI–/– mice eliminates the survival advantage. The increase in IL-6 in septic DPPI–/– mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. These results indicate that mast cell DPPI harms the septic host and that DPPI is a novel potential therapeutic target for treatment of sepsis.

Authors

Jon Mallen–St. Clair, Christine T.N. Pham, S. Armando Villalta, George H. Caughey, Paul J. Wolters

×

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors
Frédéric Preitner, … , Rémy Burcelin, Bernard Thorens
Frédéric Preitner, … , Rémy Burcelin, Bernard Thorens
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):635-645. https://doi.org/10.1172/JCI20518.
View: Text | PDF

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

  • Text
  • PDF
Abstract

The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R–/– but not in Gipr–/– mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.

Authors

Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens

×
Corrigendum
Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Guillermina Girardi, … , V. Michael Holers, Jane E. Salmon
Guillermina Girardi, … , V. Michael Holers, Jane E. Salmon
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):646-646. https://doi.org/10.1172/JCI18817C1.
View: Text | PDF | Amended Article

Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome

  • Text
  • PDF
Abstract

Authors

Guillermina Girardi, Jessica Berman, Patricia Redecha, Lynn Spruce, Joshua M. Thurman, Damian Kraus, Travis J. Hollmann, Paolo Casali, Michael C. Caroll, Rick A. Wetsel, John D. Lambris, V. Michael Holers, Jane E. Salmon

×
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts