New ways to ease liver disease
Many patients with liver diseases often encounter difficulties with therapy and ultimately require liver transplant to survive. Since many acute and chronic liver diseases are driven by immune-mediated mechanisms, there is a necessity to find new therapies that can inhibit these immune-based triggers and block liver damage. In a study appearing online on March 3 in advance of publication in the April 1 print edition of the Journal of Clinical Investigation, Christian Trautwein, Christian Klein, and colleagues from Hannover Medical School identify new therapeutic targets in liver diseases.
There has been growing evidence that IL-6 is protective against many pathophysiological conditions in the liver. IL-6 is a protein called a cytokine, which has cell protective functions. In cells, IL-6 acts by binding to a specific receptor in the cell membrane, which then triggers activation of gp130, a signal transducing protein. Gp130 leads to the activation of a signaling pathway inside cells from the membrane to the nucleus called the Jak/Stat pathway.
The researchers used rodent models of liver damage that causes hepatitis and liver damage involving immune T cells. Their aim was to characterize mechanisms involved in mediating IL-6-–dependent protection. They demonstrate that IL-6/gp130/Stat3–dependent expression of two proteins in liver cells – KC and SAA2 – is essential in mediating the protective effect of IL-6.
This establishes the role of key protective factors in liver injury mediated by hepatitis and immune mechanisms. KC and SAA2 are two proteins that may be of interest in developing therapies to treat immune-mediated liver disease in humans.
TITLE: The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-–mediated liver injury
AUTHOR CONTACT:
Christian Klein
Hannover Medical School, Hannover, Germany
Phone: 049 511 5323401; Fax: 49-511-532-5692; E-mail: klein.christian@mh-hannover.de
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Physiology
Osteopontin is swell for arthritis
Rheumatoid arthritis (RA) remains a mysterious disease, with little known about its etiology and underlying mechanisms. It clearly has an inflammatory component mediated by T cells in the surrounding inflammatory area. Osteopontin (also known as T cell activation-1) is a protein that is known to promote inflammation, and high levels of osteopontin are seen in patients with RA. Appearing online on March 3 in advance of publication in the April 1 print edition of the Journal of Clinical Investigation, a study by Jingwu Zhang and colleagues from Shanghai Second Medical University investigate the functional role of osteopontin in RA. The researchers show that osteopontin plays a central role in a feedback mechanism responsible for amplifying RA. The study increases our understanding of the role of osteopontin in inflammatory process in general and in the development of novel therapeutic strategies for RA and other inflammatory conditions.
TITLE: Role of osteopontin in amplification and perpetuation of rheumatoid synovitis
AUTHOR CONTACT:
Jingwu Z. Zhang
Baylor College of Medicine, Houston, TX USA
Phone: 713-798-3975; Fax: 713-798-5665; E-mail: jzang@bcm.tmc.edu
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Physiology
Seizing the cause of cysts in ADPKD
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney enlargement with cysts and formation of fibrous tissue, high blood pressure, and weak blood vessels in the brain. In a study appearing online on March 3 in advance of publication in the April 1 print edition of the Journal of Clinical Investigation, Toshio Mochizuki and colleagues at Hokkaido University investigate the mechanisms underlying cyst formation in a new mouse model of ADPKD. They find that the mice, which lack a gene called PDK1 (thought to be a potential cause of ADPKD) have epithelial cells that proliferate to form cysts. The cells also change shape from round to flat and the flat cells grow abnormally to form the larger cysts in the kidney characteristic of late stage ADPKD. These results are important for understanding cyst formation and function of PKD1 in kidney epithelial cells. These findings will help in the search for drugs for prevention of renal failure of ADPKD patients.
TITLE: Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation
AUTHOR CONTACT:
Toshio Mochizuki
Hokkaido University Graduate School of Medicine, Sapporo, Japan
Phone: 81-11-716-1161; Fax: 81-11-706-7710; E-mail: mtoshi@med.hokudai.ac.jp
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Metabolic Disease
Major information on MODY mutation
Mature onset diabetes of the young (MODY) is an inherited form of diabetes that can result from mutations in many different genes, including HNF-4alpha. HNF-4alpha is expressed in multiple tissues involved in glucose regulation and diabetes, but it was unknown in which organ the gene primarily contributes to MODY. In a study appearing online on March 3 in advance of publication in the April 1 print edition of the Journal of Clinical Investigation, Klaus Kaestner and colleagues from the University of Pennsylvania show that the loss of HNF-4alpha in cells of the pancreas alone is sufficient to impair glucose metabolism. By creating mice that lack HNF-4alpha specifically in pancreatic cells, the authors show that the gene is required for both normal glucose regulation and proper insulin secretion in response to glucose stimulation. They show that HNF-4alpha regulates a subunit of a potassium channel that is involved in glucose-stimulated insulin secretion. These data provide a molecular explanation for the defect in insulin secretion from the pancreas caused by HNF-4alpha mutations in MODY.
TITLE: The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion
AUTHOR CONTACT:
Klaus Kaestner
University of Pennsylvania, Philadelphia, PA USA
Phone: 215-898-8759; Fax: 215-573-5892; E-mail: kaestner@mail.med.upenn.edu
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Immunology
B cells cry for help in XLP
X-linked lymphoproliferative disease (XLP) is a rare and complex immune disorder caused by mutations in the gene that encodes the intracellular protein signaling lymphocytic activation molecule (SLAM)–associated protein (SAP). The mechanisms by which mutations in SAP cause the clinical manifestations of the disease – the low levels of plasma proteins needed for immune responses, lymphoma, and often-fatal mononucleosis infections – are unknown. Although mouse models of XLP have been generated, they have limitations due to differences in how mice and man develop the disease. In a study appearing online on March 3 in advance of the April 1 print issue of the Journal of Clinical Investigation, Stuart Tangye and colleagues from Centenary Institute investigate defects in humoral immunity in fourteen XLP patients from nine different families. They found that XLP patients have normal B cell development but a severe deficiency in the number of circulating memory B cells. This defect was due to impaired T cell help, as T cells from XLP patients had reduced production of the cytokine IL-10 and did not effectively stimulate B cell immunoglobulin production. The results identify IL-10 as a key player contributing to impaired humoral immunity in XLP and offer potential therapeutic approaches for the treatment of this immunodeficiency.
TITLE: Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
AUTHOR CONTACT:
Stuart Tangye
Centenary Institute, Newtown, Australia
Phone: 011-61-2-9565-6127; Fax: 011-61-2-9565-6103; E-mail: s.tangye@centenary.usyd.edu.au
View the PDF of this article at: https://www.the-jci.org/press/23139.pdf
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Journal
Journal of Clinical Investigation