Share:

Years and Volumes

Success! Thank you for subscribing to receive email notifications when new articles are published in Molecular Medicine 2015. Click here to manage your subscriptions.

 

Articles from this Volume

Javier Sancho-Pelluz, Joaquin Tosi, Chun-Wei Hsu, Frances Lee, Kyle Wolpert, Mirela R Tabacaru, Jonathan P Greenberg, Stephen H Tsang, and Chyuan-Sheng Lin

Rhodopsin is the G protein–coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon. D190N (RhoD190n ), a missense mutation in rhodopsin, causes autosomal-dominant retinitis pigmentosa (adRP) in humans. Affected patients present hyperfluorescent retinal rings and progressive rod photoreceptor degeneration. Studies in humans cannot reveal the molecular processes causing the earliest stages of the condition, thus necessitating the creation of an appropriate animal model. A knock-in mouse model with the D190N mutation was engineered to study the pathogenesis of the disease. Electrophysiological and histological findings in the mouse were similar to those observed in human patients, and the hyperfluorescence pattern was analogous to that seen in humans, confirming that the D190N mouse is an accurate model for the study of adRP

View article PDF

 

Posted by Leah Caracappa on Jun 20, 2012 11:20 AM CDT
Niels Eijkelkamp, Cobi J Heijnen, Anibal Garza Carbajal, Hanneke L D M Willemen, Huijing Wang, Michael S Minett, John N Wood, Manfred Schedlowski, Robert Dantzer, Keith W Kelley, and Annemieke Kavelaars

The molecular mechanisms determining magnitude and duration of inflammatory pain are still unclear. We assessed the contribution of G protein–coupled receptor kinase (GRK)-6 to inflammatory hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of cytokine-induced hyperalgesia. In GRK6–/– mice, a significantly lower dose (100 times lower) of intraplantar interleukin (IL)-1β was sufficient to induce hyperalgesia compared with wild-type (WT) mice. In addition, IL-1β hyperalgesia lasted much longer in GRK6–/– mice than in WT mice (8 d in GRK6–/– versus 6 h in WT mice). Tumor necrosis factor (TNF)- α–induced hyperalgesia was also enhanced and prolonged in GRK6–/– mice. In vitro, IL-1β–induced p38 phosphorylation in GRK6–/– dorsal root ganglion (DRG) neurons was increased compared with WT neurons. In contrast, IL-1β only induced activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway in WT neurons, but not in GRK6–/– neurons. In vivo, p38 inhibition attenuated IL-1β– and TNF-α–induced hyperalgesia in both genotypes. Notably, however, whereas PI 3-kinase inhibition enhanced and prolonged hyperalgesia in WT mice, it did not have any effect in GRK6-deficient mice. The capacity of GRK6 to regulate pain responses was also apparent in carrageenan-induced hyperalgesia, since thermal and mechanical hypersensitivity was significantly prolonged in GRK6–/– mice. Finally, GRK6 expression was reduced in DRGs of mice with chronic neuropathic or inflammatory pain. Collectively, these findings underline the potential role of GRK6 in pathological pain. We propose the novel concept that GRK6 acts as a kinase that constrains neuronal responsiveness to IL-1β and TNF-α and cytokine-induced hyperalgesia via biased cytokine-induced p38 and PI 3-kinase/Akt activation.

View article PDF
Supplementary data PDF

Posted by Leah Caracappa on Jun 20, 2012 11:19 AM CDT
David M Davies, Julie Foster, Sjoukje J C van der Stegen, Ana C Parente-Pereira, Laura Chiapero-Stanke, George J Delinassios, Sophie E Burbridge, Vincent Kao, Zhe Liu, Leticia Bosshard-Carter, May C I van Schalkwyk, Carol Box, Suzanne A Eccles, Stephen J Mather, Scott Wilkie, and John Maher

Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbBengineered 32D hematopoietic cells, we found that human T1E28z+ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28z+ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.

View article PDF
Supplementary data PDF

 

Posted by Leah Caracappa on Jun 20, 2012 11:17 AM CDT
Andreas Linkermann, Jan H Bräsen, Federica De Zen, Ricardo Weinlich, Reto A Schwendener, Douglas R Green, Ulrich Kunzendorf, and Stefan Krautwald

Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNFα-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNFα-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNFα/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP),we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis.

View article PDF
Supplementary data PDF

Posted by Leah Caracappa on Jun 20, 2012 11:14 AM CDT
Tadasuke Tsukiyama, Mayuko Matsuda-Tsukiyama1 Miyuki Bohgaki, Sayuri Terai1 Shinya Tanaka, and Shigetsugu Hatakeyam

The nuclear factor (NF)-κB family of transcription factors regulates diverse cellular functions, including inflammation, oncogenesis and apoptosis. It was reported that A20 plays a critical role in the termination of NF-κB signaling after activation. Previously, we showed that Ymer interacts and collaborates with A20, followed by degradation of receptor-interacting protein (RIP) and attenuation of NF-κB signaling. Here we show the function of Ymer in regulation of several signaling pathways including NF-κB on the basis of results obtained by using Ymer transgenic (Ymer Tg) mice. Ymer Tg mice exhibited impaired immune responses, including NF-κB and mitogen activated protein kinase (MAPK) activation, cell proliferation and cytokine production, to tumor necrosis factor (TNF)-α, polyI:C or lipopolysaccharide (LPS) stimulation. Ymer Tg mice were more resistant to LPS-induced septic shock than wild-type mice. Transgene of Ymer inhibited the onset of glomerulonephritis in lpr/lpr mice as an autoimmune disease model. In contrast to the inflammatory immune response to LPS, Fas-mediated cell death was strongly induced in liver cells of Ymer Tg mice in which Ymer is abundantly expressed. These findings suggest that Ymer acts as a regulator downstream of several receptors and that Ymer functions as a positive or negative regulator in a signaling pathway-dependent manner.

View article PDF
Supplementary data PDF

Posted by Leah Caracappa on Jun 20, 2012 11:12 AM CDT
Xiao Meng, Kai Zhang, Jingjing Li, Mei Dong, Jianmin Yang, Guipeng An, Weidong Qin, Fei Gao, Cheng Zhang, and Yun Zhang

CD4+CD25+ regulatory T cells (Tregs) mediate immune suppression and prevent autoimmune disorders. Recently, Tregs were found to present in atherosclerotic lesions and play an important role in the progression of atherosclerosis. Statins have immunomodulatory properties, and the effect of statins on atherosclerosis depends in part on their immunomodulatory mechanisms. We sought to determine whether statins exhibit an effect on Tregs in atherosclerotic plaques and in peripheral circulation of patients with acute coronary syndrome (ACS). In an in vivo experiment, we induced atherosclerotic plaques in apolipoprotein E–deficient (ApoE–/–) mice. The mice were randomly divided into two groups for 6-wk treatment: simvastatin (50 mg/kg/d) or vehicle (control). Simvastatin significantly increased the number of Tregs and the expression of Treg marker Foxp3 (Forkhead/winged helix transcription factor), transforming growth factor (TGF)-β and interleukin (IL)-10 in atherosclerotic plaques. Moreover, sim - vastatin played an important role in modulating the balance between antiinflammatory (Tregs and Th2 cells) and proinflammatory (Th17 and Th1 cells) subsets of T cells. In an in vitro experiment, peripheral blood mononuclear cells (PBMCs) were isolated from patients with ACS and incubated with simvastatin. After an incubation for 96 h, simvastatin significantly enhanced the frequency and functional suppressive properties of Tregs. Therefore, statin treatment may influence Tregs in atherosclerotic lesions. Furthermore, statins improved the quantity and suppressive function of Tregs in ACS patients.

View article PDF

 

Posted by Leah Caracappa on Jun 20, 2012 11:10 AM CDT
Blake T Gurfein, Andrew W Stamm, Peter Bacchetti, Mary F Dallman, Nachiket A Nadkarni, Jeffrey M Milush, Chadi Touma, Rupert Palme, Charles Pozzo Di Borgo, Gilles Fromentin, Rachel Lown-Hecht, Jan Pieter Konsman, Michael Acree, Mary Premenko-Lanier, Nicolas Darcel, Frederick M Hecht, and Douglas F Nixon

Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a “calm mouse model” with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

View article PDF
Supplementary data PDF

Posted by Leah Caracappa on Jun 20, 2012 11:09 AM CDT
Paola Mina-Osorio, Mauricio Rosas-Ballina, Sergio I Valdes-Ferrer, Yousef Al-Abed, Kevin J Tracey, and Betty Diamond

Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the regulatory mechanisms that coordinate cell trafficking and antibody production are still poorly understood. Here, marginal zone (MZ) B cells responding to streptococcus in the blood were observed to migrate along splenic nerves, arriving at the red pulp venous sinuses where they become antibody-secreting cells. Electrical stimulation of the vagus nerve, which in turn regulates the splenic nerve, arrested B-cell migration and decreased antibody secretion. Thus, neural circuits regulate the first wave of antibody production following B-cell exposure to blood-borne antigen.

View article PDF
Supplementary data PDF

Posted by Leah Caracappa on Jun 20, 2012 11:07 AM CDT
Nora Hagemeyer, Susann Boretius, Christoph Ott, Axel von Streitberg, Henrike Welpinghus, Swetlana Sperling, Jens Frahm, Mikael Simons, Pietro Ghezzi, and Hannelore Ehrenreich

Erythropoietin (EPO) reduces symptoms of experimental autoimmune encephalomyelitis in rodents and shows neuroregenerative effects in chronic progressive multiple sclerosis. The mechanisms of action of EPO in these conditions with shared immunological etiology are still unclear. Therefore, we used a model of toxic demyelination allowing exclusion of T cell–mediated inflammation. In a double-blind (for food/injections), placebo-controlled, longitudinal four-arm design, 8-wk-old C57BL/6 mice (n = 26/group) were assigned to cuprizone-containing (0.2%) or regular food (ground chow) for 6 wks. After 3 wks, mice were injected every other day with placebo or EPO (5,000 IU/kg intraperitoneally) until the end of cuprizone feeding. Half of the mice were exposed to behavioral testing, magnetic resonance imaging (MRI) and histology immediately after treatment cessation, whereas the other half were allowed a 3-wk treatment-free recovery. Immediately after termination of cuprizone feeding, all toxin-exposed mice were compromised regarding vestibulomotor function/coordination, with EPO-treated animals performing better than placebo. Likewise, ventricular enlargement after cuprizone, as documented by MRI, was less pronounced upon EPO. After a 3-wk recovery, remarkable spontaneous improvement was observed in all mice with no measurable further benefit in the EPO group (“ceiling effect”). Histological analysis of the corpus callosum revealed attenuation by EPO of the cuprizone-induced increase in microglial numbers and amyloid precursor protein accumulations as a readout of inflammation and axonal degeneration. To conclude, EPO ameliorates neurological symptoms in the cuprizone model of demyelination, possibly by reduction of inflammation associated axonal degeneration in white matter tracts. These findings underscore the value of future therapeutic strategies for multiple sclerosis based on EPO or EPO variants.

View article PDF

Posted by Leah Caracappa on Jun 20, 2012 10:59 AM CDT
Gwenoline Borhis, Muriel Viau, Gamal Badr, Yolande Richard, and Moncef Zouali

Protein A (SpA) of Staphylococcus aureus is known to target the paratope of immunoglobulins expressing VH3 genes, and to delete marginal zone B cells and B-1a in vivo. We have discovered that SpA endows S. aureus with the potential to subvert B-cell trafficking in the host. We found that SpA, whose Fc-binding site has been inactivated, binds essentially to naïve B cells and induces a long-lasting decrease in CXCR4 expression and in B-cell chemotaxis to CXCL12. Competition experiments indicated that SpA does not interfere with binding of CXCR4 ligands and does not directly bind to CXCR4. This conclusion is strongly supported by the inability of SpA to modulate clathrin-mediated CXCR4 internalization, which contrasts with the potent effect of anti- immunoglobin M (IgM) antibodies. Microscopy and biochemical experiments confirmed that SpA binds to the surface IgM/IgD complex and induces its clathrin-dependent internalization. Concomitantly, the SpA-induced signaling leads to protein kinase C–dependent CXCR4 downmodulation, suggesting that SpA impairs the recycling of CXCR4, a postclathrin process that leads to either degradation into lysozomes or de novo expression at the cell surface. In addition to providing novel insight into disruption of B-cell trafficking by an infectious agent, our findings may have therapeutic implications. Because CXCR4 has been associated with cancer metastasis and with certain autoimmune diseases, SpA behaves as an evolutionary tailored highly specific, chemokine receptor inhibitor that may have value in addition to conventional cytotoxic therapy in patients with various malignancies and immune-mediated diseases.

View PDF
Posted by Leah Caracappa on Jun 20, 2012 10:57 AM CDT
< Prev    1 2