Articles in 2010

Although infectious agents contribute to epilepsy, seizures can also be elicited through inflammatory pathways in sterile conditions. Vezzani and her colleagues demonstrate in both acute and chronic models of epilepsy that HMGB1, a protein normally found in the nucleus, is released by damaged or highly stressed cells and, by binding TLR4, lowers seizure threshold and increases time spent in seizures. Selective inhibition of this pathway retards seizure generation, suggesting new targets for anticonvulsant therapy (pages 369–370).

Insulin can signal through phosphotidylinositol 3-kinase (PI3K) to increase cellular growth, which often results in increased protein translation and stress of the endoplasmic reticulum (ER). Umut Ozcan and his colleagues now find that insulin signaling leads to the disassociation of p85α and p85β, the heterodimeric regulatory subunits of PI3K, allowing them to interact with and increase the nuclear localization of a key transcription factor that resolves ER stress. Thus, in states of insulin resistance, such as in prediabetes, resolution of ER stress is hampered, further exacerbating the disease (pages 374–376 and 438–445).

Interferon-β (IFN-β) is a mainstay therapy for multiple sclerosis. However, only two thirds of patients respond to therapy, and clinical symptoms worsen in some patients. Chandar Raman and his colleagues show that IFN-β alleviates disease induced by T helper type 1 cells and exacerbates disease induced by T helper type 17 cells in mice. They also show that these effects of IFN-β rely on IFN-γ signaling (pages 376–377).

Insulin signals through phosphoinositide 3-kinase (PI3K) to induce cell growth, which often increases protein translation and stress of the endoplasmic reticulum (ER). In two new studies, Umut Ozcan and Ron Kahn and their colleagues now find that in response to insulin signaling, p85α and p85β, the heterodimeric regulatory subunits of PI3K, can increase the nuclear localization of a key transcription factor that resolves ER stress (pages 374–376 and pages 429–437).

HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to antiretroviral therapy. This study shows that some hematopoietic stem cells are latently infected and may therefore constitute such a reservoir.

Programmed death-1 (PD-1) and interleukin-10 (IL-10) impair T cell function during chronic viral infections. Microbial products are now found to inhibit T cell function during HIV infection by upregulating PD-1 and IL-10 production by monocytes.

Kynurenine, a metabolite produced by the action of the enzyme indoleamine 2,3-dioxygenase on tryptophan, accumulates under inflammatory conditions and has immunomodulatory effects. This study by Yutang Wang et al. describes a new function for kynurenine as an endogenous vasodilator under conditions of systemic inflammation, such as malaria infection and endotoxemia in mice, and provides insight into the molecular mechanisms involved (pages 265–267).

Muscle spasticity is a major problem for individuals with SCI. Now, Laurent Vinay and his colleagues report that downregulation of the potassium-chloride cotransporter in spinal cord motor neurons after SCI has a key role in the development of spasticity (pages 270–271).

Metastasis is a fatal complication of prostate cancer, but its mechanisms remain largely unknown. In this report, the authors identify a signaling pathway commonly deregulated in human prostate cancer and describe how it can foster both primary growth and metastatic tumor progression. Epigenetic silencing of the RasGAP DAB2IP by EZH2 overexpression results in aberrant activation of Ras signaling, but also of NF-κB. These two events are mediated by different DAB2IP domains and have distinct roles in localized growth and distant dissemination.

The expression of blood group antigens causes deletion of cells that generate self-specific antibodies to those antigens, but this deletion could limit adaptive immunity toward pathogens bearing cognate antigens. Two innate immune lectins, galectin-4 and galectin-8, are now reported to recognize and kill human blood group antigen–expressing bacteria.

Transduced hematopoietic stem cells can benefit patients with X-linked chronic granulomatous disease (a genetic immunodeficiency), but it's not risk free. In two treated patients, insertional activation of MDS1–EVI1, PRDM16 and SETBP1 markedly increased the number of transduced cells in the blood, leading to oligoclonal hematopoiesis, monosomy 7 and a myelodysplastic syndrome (pages 163–165).

In β-thalassemia, decreased β-globin synthesis leads to red blood cell loss, iron overload and anemia. Using a mouse model of this disease, Huihui Li et al. now describe a new approach for treating β-thalassemia: injection of the iron transporter transferrin. This therapy had many beneficial effects, including reversing splenomegaly and raising red blood cell counts.

Angiotensin II contracts blood vessels and has been implicated as a causative factor in hypertension. Christophe Guilluy et al. now demonstrate that the guanine exchange factor Arghef1 is required for the hypertensive effects of angiotensin II in mice, and describe a new signaling pathway by which angiotensin II triggers Jak2-dependent activation of Arghef1 to cause smooth muscle cell contraction (pages 165–166).

The protein kinase mTOR is known to contribute to cancer development. However, existing drugs targeting mTOR, such as rapamycin, have not been very effective at inhibiting cancer cell survival and also have the unwanted side effect of immunosuppression. Studying preclinical models of leukemia driven by the BCR-ABL oncogene, Matthew Janes et al. now show that a new mTOR inhibitor—which unlike previous ones is an ATP competitive inhibitor that targets the active site of the enzyme—can overcome these drawbacks.

Variation in the IL-7 receptor is associated with susceptibility to multiple sclerosis. Jingwu Zhang and his colleagues provide an explanation. They show that the cytokine IL-7 regulates the surival and proliferation of T helper type 17 cells—a cell type known to be involved in the pathogenesis of multiple sclerosis. The findings suggest that IL-7 antagonism could be useful in individuals with autoimmune diseases such as multiple sclerosis (pages 166–168).