JCI table of contents: August 1, 2006


Marijuana use causes early pregnancy failure

Marijuana use at the time of conception and early in pregnancy prevents embryos' safe passage from the ovary to the uterus, resulting in early pregnancy failure, suggests a new study in mice. The study appears in the August issue of the Journal of Clinical Investigation.

Marijuana, the most widely used illegal drug among women of reproductive age, binds to 2 receptors – cannabinoid receptors 1 and 2 (CB1, CB2) – which are found in the brain and other organs including sperm, eggs, and newly formed embryos. Normally, these 2 receptors are activated by the naturally occurring signaling molecule anandamide. Anandamide formation by the enzyme NAPE-PLD is carefully balanced with its degradation by the enzyme FAAH, resulting in a finely tuned local "anandamide tone" in embryos and the oviduct. This balance is required for normal embryonic development, transport along the oviduct, implantation in the uterus, and full-term pregnancy.

In the current study, Sudhansu Dey and colleagues from Vanderbilt University show that suppression of FAAH activity in the embryos and oviduct elevates anandamide levels, which inhibits embryonic development and prevents embryos from completing their passage to the uterus, causing impaired fertility. They went on to show that administration to the mice of tetrahydrocannabinol (THC), the major psychoactive component of marijuana that like anandamide also binds to CB1, swamps normal anandamide tone, causing implantation of the embryo in the earliest stages of pregnancy to fail. The results of the study show that drugs such as THC persist and swamp these finely tuned signaling systems and as such the use of THC-containing drugs such as marijuana may lead to ectopic pregnancy and/or impaired fertility in women.

In an accompanying commentary Herbert Schuel from the State University of New York discusses the sobering results of this study regarding marijuana's effects on pregnancy outcome and goes on to stress that a number of drugs currently in development or in use to suppress appetite or trigger weight-loss are also known modulators of anandamide signaling and given the results presented in the current study "such drugs need to be carefully evaluated to judge their effects on women of reproductive age and those that are pregnant."

TITLE: Fatty acid amide hydrolase deficiency limits early pregnancy events

Sudhansu K. Dey
Vanderbilt University Medical Center, Nashville, Tennessee USA.
Phone: (615) 322-8642; Fax: (615) 322-4704; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=28621


TITLE: Tuning the oviduct to the anandamide tone

Herbert Schuel
State University of New York, Buffalo, New York, USA.
Phone: (716) 829-3578; Fax: (716) 829-2911; [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29424


HIV's cellular kiss of death explains loss of uninfected T cells in AIDS

Since the beginning of the AIDS epidemic in the 1980s, even before the HIV virus was identified, physicians and scientists recognized that a cardinal feature of AIDS was the loss of CD4+ T cells. These cells are killed by direct HIV infection but researchers have remained puzzled as to why uninfected CD4+ T cells also die in HIV-infected patients. Researchers at the Institut de Biologie in France have now shown that an HIV surface glycoprotein expressed by HIV-infected CD4+ T cells interacts with a receptor known as CXCR4 on the surface of uninfected CD4+ T cells, which triggers a cell signaling pathway known as autophagy, resulting in the death of uninfected T cells. The study appears in the August issue of the Journal of Clinical Investigation.

Martine Biard-Piechaczyk and colleagues co-cultured HIV-infected CD4+ T cells that express the HIV envelope glycoprotein with uninfected target cells that express CD4 and the CXC chemokine receptor CXCR4. They found that CXCR4 engagement by the HIV envelope glycoprotein activates the degradation pathway known as autophagy, causing the death of these uninfected "bystander" cells. The authors go on to show that molecules known as "short interfering RNAs" specific for two different genes involved in the autophagy pathway (beclin1 and atg7) can completely block the cell death process triggered by CXCR4 engagement by the HIV envelope glycoprotein.

In an accompanying commentary, Beth Levine from University of Texas Southwestern Medical Center discusses how this work eloquently establishes a mechanism for how the number of uninfected CD4+ T cells is likely depleted in patients with AIDS.

TITLE: Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4

Martine Biard-Piechaczyk
Institut de Biologie, Montpellier, France.
Phone: +33-467-60-86-60; Fax: +33-467-60-44-20; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=26185


TITLE: HIV and CXCR4 in a kiss of autophagic death

Beth Levine
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-2202; Fax: (214) 648-0284; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29447


Glimmer of hope for gout patients

For over 100 years we have known that the intensely painful disease gout is caused by the accumulation of monosodium urate crystals (MSU) in joints. Now, in a study appearing in the August issue of the Journal of Clinical Investigation, Kenneth Rock and colleagues from University of Massachusetts Medical School uncover how these crystal deposits are recognized by the immune system and trigger acute and painful inflammation.

Gout patients usually produce too much uric acid or are unable to efficiently excrete the uric acid excess. Rock and colleagues had previously shown that uric acid released from "damaged cells" in the body forms MSU crystals, which act as a "danger signal" that stimulates the immune response into action. The same group now shows that, in mice, MSU crystals are internalized by monocytes, resulting in the processing and maturation of the molecule pro–IL-1beta to its biologically active form IL-1beta. IL-1beta activates the IL-1beta receptor on cells around the MSU crystal–laden joints, which recruits the protein MyD88. This triggers the production of inflammatory molecules, resulting in painful joint inflammation. Surprisingly, the inflammatory reaction does not involve Toll-like receptors, which usually recognize foreign pathogens and trigger immune cell responses. In an accompanying commentary, Laurie Glimcher from Harvard Medical School comments that, "the study of the physiological function of IL-1beta in human gouty inflammation will undoubtedly provide new therapeutic tools to better manage the acute inflammation episode in patients with gout."

TITLE: MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals

Kenneth L. Rock
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Phone: (508) 856-2521; Fax: (508) 856-1094; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=28075


TITLE: Gout: new insights into an old disease

Laurie H. Glimcher
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 432-4846; Fax: (617) 432-0084; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29404


Protein passage into urine prevented by glomerular basement membrane

The glomerulus is a cluster of capillaries in the kidney through which fluids and other soluble material from the blood is filtered and processed to form urine. There has been a long debate about what component of the capillary serves as the primary size-selective sieve that retains proteins like albumin, but can allow too much protein to pass into the urine in conditions such as proteinuria. In a study appearing in the August issue of the Journal of Clinical Investigation, Jeffrey Miner and colleagues from Washington University School of Medicine show that it is the glomerular basement membrane, a key structure in the glomerulus, that acts as the intrinsic barrier to blood proteins.

The authors studied mice lacking the protein laminin beta2, which is a part of the glomerular basement membrane. In the absence of laminin beta2 the authors observed increased protein loss in the urine of these mice, before any other defects in other glomerular structures were observed. They found that the high protein loss was due to alterations in the composition of the glomerular basement membrane.

In an accompanying commentary, Marilyn Farquhar from the University of California, San Diego discusses how the results of this study will change the prevailing view that another structure of the glomerulus – the slit diaphragms – is the primary molecular sieve in the kidney, and will re-focus future research on the glomerular basement membrane and its role as an important anatomical barrier.

TITLE: Proteinuria precedes podocyte abnormalities in Lamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier

Jeffrey H. Miner
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-8235 : Fax : (314) 362-8237; E-mail: [email protected].


Michael Purdy
Office of Medical Public Affairs
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 286-0122 ; Fax: (314) 286-0199; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=28414


TITLE: The glomerular basement membrane: not gone, just forgotten

Marilyn G. Farquhar
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 534-7711; Fax: (858)
534-8549; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29488


Misbehaving macrophages in psoriasis

Psoriasis commonly appears as red, scaly, thickening patches of skin called plaques and is believed to be either an immune-mediated disorder in which T cells become active, migrate to the skin, and trigger an immune reaction causing inflammation and a rapid turnover of skin cells, or simply a fault in the skin cells themselves. Two separate studies appearing in the August issue of the Journal of Clinical Investigation, in different mouse models of psoriasis, now report that macrophages play a key role in inducing psoriasis-like skin disease.

Karin Scharffetter-Kochanek and colleagues from the University of Ulm studied a mouse model of psoriasis in which inflammation is T cell–dependent, whereas Ingo Haase and colleagues from the University of Cologne studied a T cell–independent mouse model of psoriasis. Strikingly, both groups report an important contribution by macrophages, implying that macrophages can contribute to both epithelial-based and T cell–mediated pathways of inflammation in this chronic skin disorder.

In an accompanying commentary, Rachael Clark and Thomas S. Kupper from Brigham and Women's Hospital, Boston, comment that the results of these two studies suggest that macrophages in the dermis, once activated by T cells or cytokines expressed by dendritic cells, produce large amounts of TNF-alpha, leading to psoriasis lesion formation. These authors go on to conclude that, "The underlying events that lead to macrophage recruitment and activation remain to be fully characterized and may result from either autoreactive T cells or aberrant epidermal signals. Further clarification …will lead to treatments that can strike at the true source of this chronic inflammatory skin disease."

TITLE: Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation

Ingo Haase
University of Cologne, Germany.
Phone: +49-221-478-86360; Fax: +49-221-478-5949 ; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27179


TITLE: Activated macrophages are essential in a murine model for T cell–mediated chronic psoriasiform skin inflammation

Karin Scharffetter-Kochanek
University of Ulm, Germany.
Phone: +49-731-500-21801; Fax: +49-731-500-21870; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27180


TITLE: Misbehaving macrophages in the pathogenesis of psoriasis

Thomas S. Kupper
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: (617) 525-5550; Fax: (617) 525-5571; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29441


A designer approach to regulating autoimmunity in diabetes

Type 1 diabetes is an autoimmune disorder in which the body's own immune system attacks the beta cells of the pancreas, destroying or damaging them sufficiently to reduce or impair insulin production. Therefore, shutting down the autoreactive T cells that attack beta islet cells is one therapeutic approach that researchers have been investigating. A molecule named cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is known to prevent T cell activation from getting out of control and as such researchers have been trying to identify ways in which to selectively engage and activate CTLA-4 to treat diabetes. In a study appearing in the August issue of the Journal of Clinical Investigation, Jeffrey Bluestone and colleagues from the University of California, San Francisco, designed and developed a transgenic mouse expressing an anti–CTLA-4 antibody on B cells that was capable of selectively inhibiting activated T cells and T cell–dependent B cell responses and prevented autoimmune diabetes in these animals. The study suggests that selective engagement of CTLA-4 in this manner represents a novel immunotherapeutic approach to the treatment of type 1 diabetes.

In an accompanying commentary, Mohamed H. Sayegh from Harvard Medical School discusses the potential harnessing of this "designer" approach for the prevention or cure of autoimmune diabetes.

TITLE: Inhibition of T cell activation and autoimmune diabetes using a B cell surface–linked CTLA-4 agonist

Jeffrey A. Bluestone
University of California, San Francisco, California, USA.
Phone: (415) 514-1683; Fax: (415) 564-5813; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27856


TITLE: Costimulation couture: a designer approach to regulating immunity

Mohamed H. Sayegh
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 732-5259; Fax: (617) 732-5254; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29455


Enzyme eNOS plays previously unrecognized role in anaphylactic shock

Anaphylaxis is a severe and rapid allergic reaction, and its most severe form – anaphylactic shock – can lead to death in minutes if left untreated. Anaphylactic shock can be caused by bee stings, food, medications, and latex exposure and one of the primary physical effects is dilation of blood vessels due to the production of nitric oxide (NO), resulting in dangerously low blood pressure. It is generally accepted that the enzyme inducible NO synthase (iNOS) is responsible for the excessive NO production during shock. However, in a study appearing in the August issue of the Journal of Clinical Investigation, Anje Cauwels and colleagues from Ghent University, Belgium, show that anaphylactic shock in mice was dependent entirely on NO produced not by iNOS, but by endothelial NO synthase (eNOS), which is made in endothelial cells that line blood vessels. The results show that eNOS is activated via the PI3K signaling pathway. The researchers went on to show that inhibition of NOS or PI3K, or eNOS deficiency provided complete protection against shock. The data strongly support the unexpected concept that eNOS-derived NO is the main cause of vessel dilation and low blood pressure in anaphylactic shock. In an accompanying commentary, Thomas Michel and Charles Lowenstein comment that, "these findings also suggest that inhibitors of PI3K…might plausibly be targets for the treatment of anaphylaxis."

TITLE: Anaphylactic shock depends on PI3K and eNOS-derived NO

Anje Cauwels
Ghent University and Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium.
Phone: +32-9-3313712; Fax: +32-9-3313609; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=25426


TITLE: What's in a name? eNOS and anaphylactic shock

Thomas Michel
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 732-7376; Fax: (617) 732-5132; Emal: [email protected].


Charles J. Lowenstein
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 955-1530; Fax: (410) 502-5336; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29406


Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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