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JCI online early table of contents: Jan. 12, 2009

EDITOR'S PICK: Opiods provide relief from neuropathic pain

The pain that is associated with injury to nerves, such as caused by the trauma of amputation, entrapment, and compression, is known as neuropathic pain. It can be extremely debilitating, and treatments show limited or no effectiveness. Nerve injury underlying neuropathic pain is associated with an inflammatory response, and immune cells are thought to be contributors to the pain. However, Halina Machelska and colleagues, at Freie Universitt Berlin, Germany, have now shown that in a mouse model of neuropathic pain, a substantial proportion of the immune cells at the site of nerve injury produce chemicals known as opiods that markedly reduce the symptoms of neuropathic pain. The authors therefore suggest that selectively targeting opioid-containing immune cells at sites of nerve injury could provide natural pain relief and offer a novel approach for neuropathic pain.

TITLE: Immune cellderived opioids protect against neuropathic pain in mice

Halina Machelska
Freie Universitt Berlin, Medizinische Fakultt Charit-Universittsmedizin Berlin, Berlin, Germany.
Phone: 49-30-8445-3851; Fax: 49-30-8445-3826; E-mail:

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IMMUNOLOGY: New effect on the immune system of Vitamin D3

A group of proteins known as TLRs recognize molecules produced by microorganisms such as bacteria and viruses and trigger an immune response. Several approaches to targeting one of these proteins, TLR9, are being developed to help boost the efficacy of antitumor immunotherapies and vaccines. Catherine Hawrylowicz and colleagues, at King's College London, United Kingdom, have now provided new insight into how drugs that stimulate TLR9 might be beneficial, by showing that they inhibit the function of a population of human immune cells known as IL-10secreting Tregs.

Tregs are immune cells able to dampen ongoing immune responses. They help prevent the immune system from attacking cells and tissues of the body (i.e., they help prevent autoimmue diseases such as rheumatoid arthritis) as well as innocuous inhaled substances (i.e., they help prevent allergy). They therefore have immense clinical potential. In the study, TLR9 was found to be highly expressed by a defined population of human Tregs that produce the soluble antiinflammatory factor IL-10. Specifically, IL-10secreting Tregs induced in the presence of a form of Vitamin D known as 1-alpha,25VitD3. In vitro, induction of TLR9 was mainly regulated by 1-alpha,25VitD3, and humans that ingested 1-alpha,25VitD3 were found to have more T cells expressing TLR9 and producing IL-10. Importantly, stimulation of TLR9 on 1-alpha,25VitD3-induced IL-10secreting Tregs eliminated their ability to suppress immune responses in vitro. The authors therefore suggest that TLR9 could be used to monitor the generation of 1-alpha,25VitD3-induced IL-10secreting Tregs in patients with allergy, where they are likely to be beneficial. Further, this effect might help explain the beneficial effects of the TLR9 stimulatory drugs being developed to boost the efficiacy of cancer immunotherapies and vaccines.

TITLE: Ligation of TLR9 induced on human IL-10secreting Tregs by 1-alpha,25-dihydroxyvitamin D3 abrogates regulatory function

Catherine M. Hawrylowicz
King's College London, London, United Kingdom.
Phone: 44-207-188-0598; Fax: 44-207-403-8640; E-mail:

Kate Moore
Public Relations Officer (Health Schools)
King's College London, London, United Kingdom.
Phone: 44-207-848-4334; E-mail:

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NEUROBIOLOGY: The molecule leptin causes neuropathic pain

The pain that is associated with injury to nerves is known as neuropathic pain. It can be extremely debilitating, and treatments show limited or no effectiveness. Despite this, little is known about the molecular mechanisms underlying neuropathic pain. However, Jianren Mao and colleagues, at Massachusetts General Hospital, Boston, have now identified a role for the molecule leptin, which is not produced by nerves, in neuropathic pain in rodents. They therefore suggest that it might be a new drug target for the treatment of humans with neuropathic pain

Using a rat model of neuropathic pain, it was shown that administration of a leptin antagonist to the spinal cord prevented and reversed the condition. Consistent with this, levels of leptin and one form of the leptin receptor were upregulated in parts of the spinal cord after nerve injury in the tissues. Further, neuropathic pain was reduced in mice lacking leptin and induced in healthy rats by administration of leptin to the spinal cord. The authors therefore suggest that leptin in the spinal cord has a central role in the development of neuropathic pain and that nerves and non-nerve cells interact to cause the condition.

TITLE: Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Jianren Mao
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-2338 Fax: (617) 724-8844; E-mail:

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ONCOLOGY: New group of proteins linked to cancer development and progression

Qinong Ye and colleagues, at Beijing Institute of Biotechnology, People's Republic of China, have identified new roles for a group of proteins known as FHL proteins as regulators of cancer development and progression.

In the study, FHL1, FHL2, and FHL3 were found to physically and functionally interact with the signaling proteins Smad2, Smad3, and Smad4. The functional interaction depended on the protein casein kinase 1-delta (and not the protein TGF-beta receptor) and led to activation of a tumor-suppressor gene and repression of a tumor-promoting gene. At the cellular level, FHL1, FHL2, and FHL3 inhibited the growth of a human tumor cell line both in vitro and when transplanted into mice. Importantly, analysis of tissue from human liver cancers revealed that expression of FHL proteins is often downregulated. The authors suggest that these data provide a new avenue of research for those developing drugs for the treatment of cancer.

TITLE: Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-betalike signaling pathway

Qinong Ye
Beijing Institute of Biotechnology, Beijing, People's Republic of China.
Phone: 8610-6818-0809; Fax: 8610-6824-8045; E-mail:

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VIROLOGY: Multiple mutations needed for hepatitis C virus to escape a protective human immune response

In humans there is an association between expression of the protein HLA-B27 and protection following infection with hepatitis C virus (HCV), which causes hepatitis and increases the risk of developing liver cancer. Protection has been linked to immune cells known as CD8+ T cells that recognize HLA-B27 bound to a defined fragment of the viral protein RdRp. New understanding regarding the association between expression of HLA-B27 and protection has been provided by a team of researchers in Germany, who have determined why HCV finds it hard to mutate the RdRp fragment enough to escape the CD8+ T cell immune response.

The team, led by Robert Thimme and Ralf Bartenschlager, at the University of Freiburg and the University of Heidelberg, respectively, analyzed HCV isolated from individuals that expressed HLA-B27 but were chronically infected with HCV. In these patients, the HCV had escaped the CD8+ T cell immune response by mutating several parts of the RdRp fragment of interest. Each of the mutations affected the part of the fragment recognized by the CD8+ T cells. The authors therefore conclude that HLA-B27 provides efficient protection against HCV because if the virus is to escape recognition by the CD8+ T cell immune response it must mutate the RdRp fragment several times.

TITLE: Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27restricted human immune response

Robert Thimme
University of Freiburg, Freiburg, Germany.
Phone: 49-761-270-3280; Fax: 49-761-270-3725; E-mail:

Ralf Bartenschlager
University of Heidelberg, Heidelberg, Germany.
Phone: 49-6221-56-4569; Fax: 49-6221-56-4570; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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