JCI table of contents: September 7, 2006

September 07, 2006

EDITOR'S PICK: PNP gets a pass to enter cells

Individuals unlucky enough to be born with a genetic defect that results in them having no purine nucleoside phosphorylase (PNP), an enzyme that helps get rid of unwanted material in the cell, usually die early in life from infections, autoimmunity, and cancer. There is currently no treatment for most individuals lacking PNP, in part because it is necessary to replace PNP inside their cells, a very difficult task. Now, in a study appearing online on September 7 in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from the University of Toronto have found a way to get PNP into the cells of Pnp-deficient mice.

Some proteins can enter cells because they have a domain known as a protein transduction domain (PTD). So, Eyal Grunebaum and Ana Toro attached the PTD of another protein to PNP and showed that this PTD-PNP fusion protein could enter cells when it was administered to Pnp-deficient mice. Furthermore, frequent administration of the PTD-PNP fusion protein to Pnp-deficient mice corrected most of their defects, including their immune defects. This study might be the first step to developing a treatment for individuals lacking PNP. If this technology were to prove successful it could also be applied to other diseases caused by defects in proteins inside cells.

TITLE: TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

AUTHOR CONTACT:
Eyal Grunebaum
Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
Phone: 416-813-8623; Fax: 416-813-8624; E-mail: eyal.grunebaum@sickkids.ca

View the PDF of this article at: https://www.the-jci.org/article.php?id=25052


DERMATOLOGY: Mast cells activated by CD30 keep the immune cells coming

The red, flaky patches of skin visible on individuals with atopic dermatitis and psoriasis are caused by an ongoing immune reaction in the skin. Large numbers of T cells (one of the immune cell types that causes the skin irritation) expressing a protein known as CD30 on their surface accumulate in the damaged skin, but whether this is important for the disease has not been determined. Now, in a study using human cells and skin biopsies, which appears online on September 7 in advance of publication in the October print issue of the Journal of Clinical Investigation, Gunnar Nilsson and colleagues at the Karolinska Institute, Sweden, have shown that human mast cells (another immune cell type) are activated by CD30 to produce large amounts of the soluble factor IL-8, which is known to attract immune cells. In the inflamed skin of individuals with atopic dermatitis and psoriasis, mast cells were the predominant cell expressing the CD30 binding partner CD30L. This study provides new insight into the mechanisms of atopic dermatitis and psoriasis, as it suggests that the production of immune cell-recruiting factors by mast cells activated through CD30L helps maintain the ongoing immune reaction at the site of skin irritation by recruiting yet more immune cells to the area.

TITLE: Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion

AUTHOR CONTACT:
Gunnar Nilsson
Karolinska Institute, Stockholm, Sweden.
Phone: +46-8-517-70205; Fax: 46-8-335724; E-mail: Gunnar.P.Nilsson@ki.se.

Katarina Sternudd
Press Officer
Karolinska Institute, Stockholm, Sweden.
Phone: 46-8-524-83895; E-mail: Katarina.Sternudd@ki.se.

Pirkko Mantere
Communication Secretary
University of Kuopio, Kuopio, Finland.
Phone: 358-17-162138; E-mail: pirkko.mantere@uku.fi.

View the PDF of this article at: https://www.the-jci.org/article.php?id=24274


CARDIOVASCULAR BIOLOGY: SR-BI provides protection outside the liver

Cholesterol is naturally removed from the body through the liver. This occurs when a protein known as scavenger receptor BI (SR-BI) on the surface of cells in the liver recognizes cholesterol in combination with particles known as high-density lipoprotein. Mice lacking SR-BI have very high levels of cholesterol and, like humans with high levels of cholesterol, have a high risk of developing heart disease. However, because cells other than liver cells express SR-BI, scientists did not know whether loss of SR-BI in liver cells or other cells caused this increased risk of heart disease.

In a study appearing online on September 7, in advance of publication in the October print issue of the Journal of Clinical Investigation, Thierry Huber and colleagues from Hôpital de la Pitié, France, show that although mice lacking SR-BI only in the liver have a much higher risk of developing heart disease than normal mice, they develop less severe disease than mice lacking SR-BI in all cells. Surprisingly, mice lacking SR-BI only in the liver and mice lacking SR-BI in all cells had similarly high levels of cholesterol. This study therefore indicates that SR-BI has a role in protecting against heart disease that is not related to its cholesterol clearing function in the liver, but more studies are needed to understand what this role is.

TITLE: Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in the liver and peripheral tissues

AUTHOR CONTACT:
Thierry Huby
Hôpital de la Pitié, Paris, France.
Phone: 33-142-17-78-60; Fax: 33-145-82-81-98; E-mail: huby@chups.jussieu.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=26893


DERMATOLOGY: PKC-alpha directs neutrophil traffic to the skin

Psoriasis is a disease characterized by areas of inflammation in the skin. But exactly what causes the inflammatory cells to enter the skin is still being determined. Using a mouse model of skin inflammation, Stuart Yuspa and colleagues from the National Cancer Institute show that cells in the skin known as keratinocytes produce two types of soluble factor that work independently to recruit neutrophils (which are one of the first inflammatory cell types recruited) to the skin. Production of both these soluble factors was controlled by a signaling pathway activated by a protein known as PKC-alpha. Importantly, inhibiting PKC-alpha reduced the recruitment of neutrophils to the skin in mice and reduced the production of neutrophil-attracting soluble factors by keratinocytes from individuals with psoriasis. This study, which appears online on September 7 in advance of publication in the October print issue of the Journal of Clinical Investigation, provides insight into the mechanisms behind the recruitment of an important inflammatory cell type to the skin in a mouse model of skin inflammation and the authors suggest that blocking PKC-alpha and/or these soluble factors might be a good treatment for inflammatory skin diseases with similar characteristics in humans, such as pustular psoriasis.

TITLE: CXCR2 ligands and G-CSF mediate PKC-alpha-induced intraepidermal inflammation

AUTHOR CONTACT:
Stuart H. Yuspa
National Cancer Institute, Bethesda, Maryland, USA.
Phone: 301-496-2162; Fax: 301-496-8709; E-mail: yuspas@mail.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27514
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JCI Journals

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