JCI online early table of contents: Aug. 9, 2010

Autoimmune disorders, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), occur when an individual's immune system turns on other cells in the body. Inappropriate and excessive production of the soluble immune mediators IL-17 and IL-21 have been linked to several autoimmune disorders. Understanding the molecular mechanisms underlying this aberrant production might identify new therapeutic targets. A team of researchers, led by Alessandra Pernis, at Columbia University, New York, has now generated data in mice indicating that the protein ROCK2 might be a good therapeutic target in this context. A key piece of evidence to support this idea was the observation that administration of a ROCK inhibitor to mice with spontaneous disease that models either RA or SLE, decreased production of IL-17 and IL-21 and ameliorated disease symptoms.

TITLE: Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice

AUTHOR CONTACT:
Alessandra B. Pernis
Hospital for Special Surgery, New York, New York, USA.
Phone: 212.606.1612; Fax: 212.717.1192; E-mail: pernisa@hss.edu.

View this article at: http://www.jci.org/articles/view/42856?key=a185dbbe85d076325707

A subpopulation of cells in a tumor that are known as cancer stem cells (CSCs) are thought to be involved in tumor resistance to chemo/radiation therapy as well as tumor relapse and progression. However, whether CSCs exist in many cancers and what their identity is has been hard to determine. A team of researchers, led by Masaki Mori, at Osaka University, Japan, has now determined that CD13 is a marker for CSCs in human liver cancer cell lines and clinical samples. Furthermore, combining a CD13 inhibitor with the chemotherapeutic agent 5-FU drastically reduced tumor volume compared with either agent alone in mouse xenograft models, leading the authors to suggest that targeting the CD13+ CSCs might provide a way to treat patients with liver cancer.

TITLE: CD13 is a therapeutic target in human liver cancer stem cells

AUTHOR CONTACT:
Masaki Mori
Graduate School of Medicine, Osaka University, Osaka, Japan.
Phone: 81.6.6879.3251; Fax: 81.6.6879.3259; E-mail: mmori@gesurg.med.osaka-u.ac.jp.

View this article at: http://www.jci.org/articles/view/42550?key=c56cc5907df6fed26bed

In several clinical trials, RNAi-based therapies have been shown to be effective and well tolerated. However, animal studies suggest that there is a need for caution, as RNAi can trigger cell death leading to organ failure and lethality. It is believed that these adverse effects are a result of saturation of endogenous cellular RNAi factors such as Xpo-5. A team of researchers, led by Mark Kay, at Stanford University, California, has now generated substantive data in mice to support the idea that RNAi-based therapies overload the endogenous RNAi pathway to cause liver damage, and developed ways to overcome this problem.

In the study, members of the human Ago family of proteins were found to be involved in saturation of endogenous cellular RNAi, with Ago-2 particularly prone to saturation and acting as a rate-limiting determinant of both in vitro and in vivo RNAi efficacy, toxicity, and persistence. The authors then developed two ways to enhance RNAi efficacy and persistence while decreasing toxicity, approaches that they hope will improve human RNAi-based therapies. First, in adult mice, vector-based Ago-2/Xpo-5 coexpression enhanced RNAi silencing in the liver, reduced liver damage, and extended RNAi stability. Second, minimizing shRNA expression reduced liver damage while still permitting long-term gene silencing.

TITLE: Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver

AUTHOR CONTACT:
Mark A. Kay
Stanford University, Stanford, California, USA.
Phone: 650.498.6531; Fax: 650.498.6540; E-mail: markay@stanford.edu.

View this article at: http://www.jci.org/articles/view/43565?key=c95af59384f5118a7306

Some cancers can be divided into subtypes depending on the signaling pathways that drive tumor development. This can help determine which therapy is most appropriate, for example breast cancers lacking expression of the proteins to which hormones bind do not respond to hormone-based therapies. A team of researchers, led by Rama Khokha, at Ontario Cancer Institute, Toronto, has now generated a new mouse model of osteosarcoma (the most common type of bone tumor) and found that deletions of the Prkar1a gene characterize a molecularly distinct subtype of mouse osteosarcoma featuring overexpression of the protein RANKL. Human tumors could also be divided based on high and low expression of PRKAR1A, with low levels of expression being associated with a greater likelihood of responding to chemotherapy. The authors therefore conclude that information gleaned in mice can help divide human tumors into clinically relevant subtypes.

TITLE: Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice

AUTHOR CONTACT:
Rama Khokha
Ontario Cancer Institute, Toronto, Ontario, Canada.
Phone: 416.946.2051; Fax: 416.246.2984; E-mail: rkhokha@uhnres.utoronto.ca.

View this article at: http://www.jci.org/articles/view/42391?key=d3f1b643b774ad1a99e7

Drugs that target the protein MR are used to treat diseases of the blood vessels and heart (i.e., cardiovascular diseases). Although some of their benefit is a result of blocking binding of the steroid hormone aldosterone to MR, data indicate that some of their effects are aldosterone independent. A team of researchers, led by Richard Mortensen, at the University of Michigan Medical School, Ann Arbor, and Sheng Zhong Duan, at Shanghai Institutes for Biological Sciences, China, has now shown that mice lacking MR on immune cells known as myeloid cells are protected against heart and blood vessel damage in the same way that mice treated with drugs targeting MR are. Further analysis indicated that MR on myeloid cells is necessary for efficient classical activation of myeloid immune cells known as macrophages by proinflammatory cytokines. These data provide new insight into the mechanisms underlying the beneficial effects of drugs that target MR.

TITLE: Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice

AUTHOR CONTACT:
Richard M. Mortensen
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: 734.763.2021; Fax: 734.936.8813; E-mail: rmort@umich.edu.

Sheng Zhong Duan
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Phone: 86.21.54922000; Fax: 86.21.54920291; E-mail: duansz2008@gmail.com.

View this article at: http://www.jci.org/articles/view/41080?key=38745bc49eb24a0378fa