bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IFN-Inducible GTPase LRG47 (Irgm1) Negatively Regulates TLR4-Triggered Proinflammatory Cytokine Production and Prevents Endotoxemia
Authors: Bafica Andre , Feng Carl G. , Santiago Helton C. , Aliberti Julio , Cheever Allen , Thomas Karen E. , Taylor Gregory A. , Vogel Stefanie N. , Sher Alan 
Published: April 2014

Abstract
LRG47/Irgm1, a 47-kDa IFN-inducible GTPase, plays a major role in regulating host resistance as well as the hemopoietic response to intracellular pathogens. LRG47 expression in macrophages has been shown previously to be stimulated in vitro by bacterial LPS, a TLR4 ligand. In this study, we demonstrate that induction of LRG47 by LPS is not dependent on MyD88 signaling, but rather, requires STAT-1 and IFN-β. In addition, LRG47-deficient mice are highly susceptible to LPS, but not TLR2 ligand-induced shock, an outcome that correlates with enhanced proinflammatory cytokine production in vitro and in vivo. Further analysis revealed that LPS-stimulated LRG47-deficient macrophages display enhanced phosphorylation of p38, a downstream response associated with TLR4/MyD88 rather than IFN-β/STAT-1 signaling. In contrast, LPS-induced phosphorylation of IFN regulatory factor-3 and expression of IFN-β or the type I IFN-regulated genes, CCL5 and CCL10, were unaltered in LRG47−/− cells. Together, these observations indicate that in LPS-stimulated murine macrophages LRG47 is induced by IFN-β and negatively regulates TLR4 signaling to prevent excess proinflammatory cytokine production and shock. Thus, our findings reveal a new host-protective function for this GTPase in the response to pathogenic encounter.
Dual T Cell Receptor Expressing CD8+ T Cells with Tumor- and Self-Specificity Can Inhibit Tumor Growth without Causing Severe Autoimmunity
Authors: Weinhold Monika , Sommermeyer Daniel , Uckert Wolfgang , Blankenstein Thomas 
Published: April 2014

Abstract
The engineering of Ag-specific T cells by expression of TCR genes is a convenient method for adoptive T cell immunotherapy. A potential problem is the TCR gene transfer into self-reactive T cells that survived tolerance mechanisms. We have developed an experimental system with T cells that express two TCRs with defined Ag-specificities, one recognizing a tumor-specific Ag (LCMV-gp33), the other recognizing a self-Ag in the pancreas (OVA). By using tumor cells expressing high and low amounts of Ag and mice expressing high and low levels of self-Ag in the pancreas (RIP-OVA-Hi and RIP-OVA-Lo), we show that 1) tumor rejection requires high amount of tumor Ag, 2) severe autoimmunity requires high amount of self-Ag, and 3) if Ag expression on tumor cells is sufficient and low in the pancreas, successful adoptive T cell therapy can be obtained in the absence of severe autoimmunity. These results are shown with T cells from dual TCR transgenic mice or T cells that were redirected by TCR gene transfer. Our data demonstrate that the approach of adoptively transferring TCR redirected T cells can be effective without severe side effects, even when high numbers of T cells with self-reactivity were transferred.
Hematin Promotes Complement Alternative Pathway-Mediated Deposition of C3 Activation Fragments on Human Erythrocytes: Potential Implications for the Pathogenesis of Anemia in Malaria
Authors: Pawluczkowycz Andrew W. , Lindorfer Margaret A. , Waitumbi John N. , Taylor Ronald P. 
Published: April 2014

Abstract
Childhood malaria caused by Plasmodium falciparum is often characterized by severe anemia at low parasite burdens; the mechanism(s) responsible for this pathology remain to be defined. We have reported, based on clinical observations and in vitro models, that complement control proteins on erythrocytes such as CR1, the immune adherence receptor specific for C3b, may be reduced in childhood malaria, suggesting a possible role for complement in erythrocyte destruction. Intravascular lysis of iE by P. falciparum leads to release of erythrocyte breakdown products such as hemoglobin and hematin, which have inflammatory properties. In the present article, we demonstrate that in serum and in anticoagulated whole blood, moderate concentrations of hematin activate the alternative pathway of complement and promote deposition of C3 activation and breakdown products on erythrocytes. The degree of C3 fragment deposition is directly correlated with erythrocyte CR1 levels, and erythrocytes opsonized with large amounts of C3dg form rosettes with Raji cells, which express CR2, the C3dg receptor which is expressed on several types of B cells in the spleen. Thus, the reaction mediated by hematin promotes opsonization and possible clearance of the youngest (highest CR1) erythrocytes. A mAb specific for C3b, previously demonstrated to inhibit the alternative pathway of complement, completely blocks the C3 fragment deposition reaction. Use of this mAb in nonhuman primate models of malaria may provide insight into mechanisms of erythrocyte destruction and thus aid in the development of targeted therapies based on inhibiting the alternative pathway of complement.
Impaired T Cell Protein Kinase Cδ Activation Decreases ERK Pathway Signaling in Idiopathic and Hydralazine-Induced Lupus
Authors: Gorelik Gabriela , Fang Jing Yuan , Wu Ailing , Sawalha Amr H. , Richardson Bruce 
Published: April 2014

Abstract
T cells from patients with lupus or treated with the lupus-inducing drug hydralazine have defective ERK phosphorylation. The reason for the impaired signal transduction is unknown but important to elucidate, because decreased T cell ERK pathway signaling causes a lupus-like disease in animal models by decreasing DNA methyltransferase expression, leading to DNA hypomethylation and overexpression of methylation-sensitive genes with subsequent autoreactivity and autoimmunity. We therefore analyzed the PMA stimulated ERK pathway phosphorylation cascade in CD4+ T cells from patients with lupus and in hydralazine-treated cells. The defect in these cells localized to protein kinase C (PKC)δ. Pharmacologic inhibition of PKCδ or transfection with a dominant negative PKCδ mutant caused demethylation of the TNFSF7 (CD70) promoter and CD70 overexpression similar to lupus and hydralazine-treated T cells. These results suggest that defective T cell PKCδ activation may contribute to the development of idiopathic and hydralazine-induced lupus through effects on T cell DNA methylation.
Calcineurin Inhibitors Block MHC-Restricted Antigen Presentation In Vivo
Authors: Lee Young-Hee , Lee Young-Ran , Im Sun-A , Park Sun-Im , Kim Ki-Hyang , Gerelchuluun Turmunkh , Song Sukgil , Kim Kyungjae , Lee Chong-Kil 
Published: April 2014

AbstractAPCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.
Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E
Authors: Kakehashi Hiroe , Nishioku Tsuyoshi , Tsukuba Takayuki , Kadowaki Tomoko , Nakamura Seiji , Yamamoto Kenji 
Published: April 2014

AbstractThe aspartic proteinase cathepsin E is localized mainly in the endosomal structures of APCs and has been implicated in a variety of immune responses, however, the precise roles of cathepsin E in these cells remain speculative. In this study, we report the effect of disrupting the gene encoding cathepsin E on the nature and functions of dendritic cells (DCs) and macrophages derived from mouse bone marrow precursors, as well as mouse peritoneal macrophages. Whereas cathepsin E deficiency induced the accumulation of the lysosome-associated membrane protein (LAMP)-1 and LAMP-2 and elevated the lysosomal pH in macrophages, it did not have these effects on DCs. Although cathepsin E deficiency also caused a marked decrease in degradation of phagocytosed OVA and chemotactic responses to MCP-1 and fMLP by macrophages, these abilities were little affected in DCs by the absence of cathepsin E. Interestingly, cathepsin E deficiency markedly decreased the ability of macrophages to present intact OVA, as well as an OVA-derived antigenic peptide (266–281), to cognate T cells, while that of DCs was inversely enhanced by the absence of this protein. This paradox was resolved, in part, by the enhanced phagocytic activity and the increased expression of the costimulatory molecules CD86, CD80, and CD40, which amplify the response of T cells, in cathepsin E-deficient DCs compared with the wild-type cells. These results indicate that cathepsin E differentially regulates the nature and function of DCs and macrophages.
High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines
Authors: Zhao Yangbing , Bennett Alan D. , Zheng Zhili , Wang Qiong J. , Robbins Paul F. , Yu Lawrence Y. L. , Li Yi , Molloy Peter E. , Dunn Steven M. , Jakobsen Bent K. , Rosenberg Steven A. , Morgan Richard A. 
Published: April 2014

AbstractWe examined the activity of human T cells engineered to express variants of a single TCR (1G4) specific for the cancer/testis Ag NY-ESO-1, generated by bacteriophage display with a wide range of affinities (from 4 μM to 26 pM). CD8+ T cells expressing intermediate- and high-affinity 1G4 TCR variants bound NY-ESO-1/HLA-A2 tetramers with high avidity and Ag specificity, but increased affinity was associated with a loss of target cell specificity of the TCR gene-modified cells. T cells expressing the highest affinity TCR (KD value of 26 pM) completely lost Ag specificity. The TCRs with affinities in the midrange, KD 5 and 85 nM, showed specificity only when CD8 was absent or blocked, while the variant TCRs with affinities in the intermediate range—with KD values of 450 nM and 4 μM—demonstrated Ag-specific recognition. Although the biological activity of these two relatively low-affinity TCRs was comparable to wild-type reactivity in CD8+ T cells, introduction of these TCR dramatically increased the reactivity of CD4+ T cells to tumor cell lines.
Differential Type I IFN-Inducing Abilities of Wild-Type versus Vaccine Strains of Measles Virus
Authors: Shingai Masashi , Ebihara Takashi , Begum Nasim A. , Kato Atsushi , Honma Toshiki , Matsumoto Kenji , Saito Hirohisa , Ogura Hisashi , Matsumoto Misako , Seya Tsukasa 
Published: April 2014

Abstract
Laboratory adapted and vaccine strains of measles virus (MV) induced type I IFN in infected cells. The wild-type strains in contrast induced it to a far lesser extent. We have investigated the mechanism for this differential type I IFN induction in monocyte-derived dendritic cells infected with representative MV strains. Laboratory adapted strains Nagahata and Edmonston infected monocyte-derived dendritic cells and activated IRF-3 followed by IFN-β production, while wild-type MS failed to activate IRF-3. The viral IRF-3 activation is induced within 2 h, an early response occurring before protein synthesis. Receptor usage of CD46 or CD150 and nucleocapsid (N) protein variations barely affected the strain-to-strain difference in IFN-inducing abilities. Strikingly, most of the IFN-inducing strains possessed defective interference (DI) RNAs of varying sizes. In addition, an artificially produced DI RNA consisting of stem (the leader and trailer of MV) and loop (the GFP sequence) exhibited potential IFN-inducing ability. In this case, however, cytoplasmic introduction was needed for DI RNA to induce type I IFN in target cells. By gene-silencing analysis, DI RNA activated the RIG-I/MDA5-mitochondria antiviral signaling pathway, but not the TLR3-TICAM-1 pathway. DI RNA-containing strains induced IFN-β mRNA within 2 h while the same recombinant strains with no DI RNA required &gt;12 h postinfection to attain similar levels of IFN-β mRNA. Thus, the stem-loop structure, rather than full genome replication or specific internal sequences of the MV genome, is required for an early phase of type I IFN induction by MV in host cells.
SalmonellaFlagellin Induces Bystander Activation of Splenic Dendritic Cells and Hinders Bacterial Replication In Vivo
Authors: Salazar-Gonzalez Rosa-Maria , Srinivasan Aparna , Griffin Amanda , Muralimohan Guruprasaadh , Ertelt James M. , Ravindran Rajesh , Vella Anthony T. , McSorley Stephen J. 
Published: April 2014

AbstractBacterial flagellin is a target of innate and adaptive immune responses during Salmonella infection. Intravenous injection of Salmonella flagellin into C57BL/6 mice induced rapid IL-6 production and increased expression of activation markers by splenic dendritic cells. CD11b+, CD8α+, and plasmacytoid dendritic cells each increased expression of CD86 and CD40 in response to flagellin stimulation, although CD11b+ dendritic cells were more sensitive than the other subsets. In addition, flagellin caused the rapid redistribution of dendritic cells from the red pulp and marginal zone of the spleen into the T cell area of the white pulp. Purified splenic dendritic cells did not respond directly to flagellin, indicating that flagellin-mediated activation of splenic dendritic cells occurs via bystander activation. IL-6 production, increased expression of activation markers, and dendritic cell redistribution in the spleen were dependent on MyD88 expression by bone marrow-derived cells. Avoiding this innate immune response to flagellin is important for bacterial survival, because Salmonella-overexpressing recombinant flagellin was highly attenuated in vivo. These data indicate that flagellin-mediated activation of dendritic cells is rapid, mediated by bystander activation, and highly deleterious to bacterial survival.
Prostaglandin I2-IP Signaling Blocks Allergic Pulmonary Inflammation by Preventing Recruitment of CD4+ Th2 Cells into the Airways in a Mouse Model of Asthma
Authors: Jaffar Zeina , Ferrini Maria E. , Buford Mary C. , FitzGerald Garret A. , Roberts Kevan 
Published: April 2014

AbstractPGI2 plays a key role in limiting Th2-mediated airway inflammation. In studies to investigate the mechanism underlying such regulation, we found that the PGI2 receptor, IP, is preferentially expressed by effector CD4+ Th2 cells, when compared with Th1 cells. Adoptive transfer of DO11.10 Th2 cells pretreated with PGI2 resulted in considerably attenuated pulmonary inflammation and airway hyperreactivity in BALB/c recipient mice in response to OVA inhalation. This suppression was independent of increased cAMP levels, because pretreatment of Th2 cells with dibutyryl cAMP before transfer had no effect on airway inflammation. Moreover, PGI2 pretreatment of Th2 cells suppressed the ability of the cells to infiltrate the lungs but not the spleen. In vitro studies showed that PGI2 did not affect IL-4 and IL-5 production or the level of IFN-γ by the T cells. However, the prostanoid strongly inhibited CCL17-induced chemotaxis of CD4+ Th2 but not Th1 cells. The IP was implicated in this process since migration of wild-type Th2 cells in response to CCL17 was markedly reduced following treatment with PGI2, whereas IP-deficient Th2 cells were unaffected and migrated effectively. Collectively, these experiments suggest that PGI2, which is generated by endothelial cells during lung inflammatory response, serves to limit the influx of Th2 cells to the airways. Our results identify PGI2-IP as an important pathway for inhibiting allergic pulmonary inflammation by controlling recruitment of CD4+ Th2 cells into the inflammatory site.
Urocortin Modulates Inflammatory Response and Neurotoxicity Induced by Microglial Activation
Authors: Wang Mei-Jen , Lin Shinn-Zong , Kuo Jon-Son , Huang Hsin-Yi , Tzeng Shih-Fang , Liao Chia-Hsin , Chen Der-Cherng , Chen Wu-Fu 
Published: April 2014

Abstract
Microglia are the major inflammatory cells in the brain. Recent studies have highlighted the reciprocal roles of other brain cells in modulating the microglial inflammatory responses. Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. In the present study, we demonstrated that expression of UCN in rat substantia nigra was found to be localized principally to dopaminergic neurons. In cell culture models, the CRH receptors were expressed in microglia, and CRHR expression was up-regulated by treatment with LPS. Thus, it might be proposed that UCN regulates cellular communication between dopaminergic neurons and microglia. We show that femtomolar concentrations of UCN could inhibit LPS-induced TNF-α production in cultured microglia. Investigation of the underlying signaling pathway that mediated the anti-inflammatory effect of UCN the involved PI3K/Akt and glycogen synthase kinase-3β pathway, but not cAMP pathway. Furthermore, UCN protected dopaminergic neurons against LPS-induced neurotoxicity by inhibiting microglial activation in LPS-treated mesencephalic neuron-glia cultures. These results suggest that endogenous UCN and its receptors might be involved in a complex network of paracrine interaction between dopaminergic neurons and glia.
Heat Shock Protein 90 Associates with Monarch-1 and Regulates Its Ability to Promote Degradation of NF-κB-Inducing Kinase
Authors: Arthur Janelle C. , Lich John D. , Aziz Ramy K. , Kotb Malak , Ting Jenny P.-Y. 
Published: April 2014

Abstract
Monarch-1/NLRP12 is expressed in myeloid cells and functions as a negative regulator of inflammation by inducing proteasome-mediated degradation of NF-κB-inducing kinase. Monarch-1 is a member of the CATERPILLER gene family, also known as the nucleotide-binding domain leucine-rich repeat gene family. This family shares strong structural homology to major immune regulators expressed in lower organisms, including plants. In plants, these disease-resistance proteins (R proteins) sense pathogenic insult and initiate a protective response to limit pathogen growth. To perform this role, many R proteins require the highly conserved chaperone molecule, heat shock protein (Hsp) 90. Using a two-dimensional gel/mass spectrometry system, we detected the association of the nucleotide-binding domain leucine-rich repeat protein Monarch-1 with heat shock proteins. Further analysis indicates that analogous to plant R proteins, Hsp90 is required for Monarch-1 activity. In human monocytes, Monarch-1 associates with Hsp90, and these complexes are sensitive to treatment with specific Hsp90 inhibitors. Disruption of these complexes results in rapid degradation of Monarch-1 via the proteasome and prevents Monarch-1-induced proteolysis of NF-κB-inducing kinase. This demonstrates that Hsp90 is a critical regulator of Monarch-1 anti-inflammatory activity.
Cutting Edge: Rapid Accumulation of Epidermal CCL27 in Skin-Draining Lymph Nodes following Topical Application of a Contact Sensitizer Recruits CCR10-Expressing T Cells
Authors: Huang Victor , Lonsdorf Anke S. , Fang Lei , Kakinuma Takashi , Lee Vivian C. , Cha Emily , Zhang Hong , Nagao Keisuke , Zaleska Marzanna , Olszewski Waldemar L. , Hwang Sam T. 
Published: April 2014

Abstract
CC chemokine receptor 10 and its ligand, CCL27, are important components of T cell-mediated cutaneous immunity, but whether they influence lymph node (LN) homing by T cells is unknown. In this study, CCL27 protein was detected in skin-draining LN by Western blotting and ELISA although CCL27 mRNA transcripts were low. CCL27 protein was present at higher levels in skin-draining LN compared with gut-draining LN and spleen. A single topical treatment of mouse skin with the contact sensitizer 2,4-dinitro-1-fluorobenzene (DNFB) resulted in a 13-fold increase in CCL27 protein accumulation in skin-draining LN within 1 h and a 5-fold elevation in CCR10 mRNA (normalized to the T cell marker CD2) within 6 h. DNFB treatment also resulted in rapid depletion of ∼75% of CCL27 from the epidermis. In summary, we describe a novel mechanism for the recruitment of CCR10-positive T cells to skin-draining LN following the rapid release of preformed CCL27 from the epidermis.
HIV-Induced Changes in T Cell Signaling Pathways
Authors: Schweneker Marc , Favre David , Martin Jeffrey N. , Deeks Steven G. , McCune Joseph M. 
Published: April 2014

Abstract
Infection with HIV usually results in chronic activation of the immune system, with profound quantitative and qualitative changes in the T cell compartment. To better understand the mechanistic basis for T cell dysfunction and to discern whether such mechanisms are reversed after effective antiviral treatment, we analyzed changes in signaling pathways of human CD4+ and CD8+ T cells from 57 HIV-infected subjects in varying stages of disease progression and treatment, including long-term nonprogressors, progressors, and chronically infected subjects provided effective antiretroviral therapy (responders). A previously described PhosFlow method was adapted and optimized so that protein phosphorylation could be visualized in phenotypically defined subpopulations of CD4+ and CD8+ T cells (naive, memory, and effector) by flow cytometry. T cell signaling induced by TCR cross-linking, IL-2, or PMA/ionomycin was found to be blunted within all T cell subpopulations in those with progressive HIV disease compared with long-term nonprogressors and responders. Although alterations in cellular signaling correlated with levels of basal phosphorylation, viral load, and/or expression of programmed death-1, it was the level of basal phosphorylation that appeared to be the factor most dominantly associated with impaired signaling. Notably, provision of effective antiretroviral therapy was associated with a normalization of both basal phosphorylation levels and T cell signaling. These data, in aggregate, suggest that generalized dysfunction of the T cell compartment during progressive HIV disease may be in part dependent upon an increased basal level of phosphorylation, which itself may be due to the heightened state of immune activation found in advanced disease.
T Cell Ig and Mucin Domain-1-Mediated T Cell Activation Requires Recruitment and Activation of Phosphoinositide 3-Kinase
Authors: de Souza Anjali J. , Oak Jean S. , Jordanhazy Ryan , DeKruyff Rosemarie H. , Fruman David A. , Kane Lawrence P. 
Published: April 2014

Abstract
Ligation of the transmembrane protein T cell Ig and mucin domain (Tim)-1 can costimulate T cell activation. Agonistic Abs to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or costimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in a lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI3K. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation.