bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF-α Is a Positive Regulatory Factor for Human Vγ2Vδ2 T Cells
Authors: Li Haishan , Luo Kun , Pauza C. David 
Published: April 2014

AbstractVγ2Vδ2 T cells in human peripheral blood recognize phosphoantigen and play important roles in host defense and immunoregulation. The TCR is required for Vγ2Vδ2 T cell responses to phosphoantigen, but less is known about soluble or cell-associated costimulatory molecules. In this study, we show that human Vγ2Vδ2 T cell responses to phosphoantigen, including activation, proliferation, cytokine production, and tumor cell cytotoxicity, require TNF-α binding to its receptor, with a preference for TNFR2. Because stimulated Vγ2Vδ2 cells also produce TNF-α, this may be a positive control mechanism to sustain the response. Impaired proliferation in the presence of TNF-α or TNFR blocking agents was partially rescued by a TLR2 agonist, Pam3Cys. Our studies demonstrate that TNF-α plays a critical role in regulating human Vγ2Vδ2 T cell immune responses.
Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma
Authors: Henry Emmanuelle , Desmet Christophe J. , Garzé Virginie , Fiévez Laurence , Bedoret Denis , Heirman Carlo , Faisca Pedro , Jaspar Fabrice J. , Gosset Philippe , Jacquet Alain P. A. , Desmecht Daniel , Thielemans Kris , Lekeux Pierre , Moser Muriel , Bureau Fabrice 
Published: April 2014

Abstract
Dendritic cells (DCs) are professional APCs that have a unique capacity to initiate primary immune responses, including tolerogenic responses. We have genetically engineered bone marrow-derived DCs to express the immunosuppressive cytokine IL-10 and tested the ability of these cells to control experimental asthma. A single intratracheal injection of OVA-pulsed IL-10-transduced DCs (OVA-IL-10-DCs) to naive mice before OVA sensitization and challenge prevented all of the cardinal features of airway allergy, namely, eosinophilic airway inflammation, airway hyperreactivity, and production of mucus, Ag-specific Igs, and IL-4. OVA-IL-10-DCs also reversed established experimental asthma and had long-lasting and Ag-specific effects. We furthermore showed, by using IL-10-deficient mice, that host IL-10 is required for mediating the immunomodulatory effects of OVA-IL-10-DCs and demonstrated a significant increase in the percentage of OVA-specific CD4+CD25+Foxp3+IL-10+ regulatory T cells in the mediastinal lymph nodes of OVA-IL-10-DC-injected mice. Finally, adoptive transfer of CD4+ mediastinal lymph node T cells from mice injected with OVA-IL-10-DCs protected OVA-sensitized recipients from airway eosinophilia upon OVA provocation. Our study describes a promising strategy to induce long-lasting Ag-specific tolerance in airway allergy.
Mechanisms of Oncostatin M-Induced Pulmonary Inflammation and Fibrosis
Authors: Mozaffarian Afsaneh , Brewer Avery W. , Trueblood Esther S. , Luzina Irina G. , Todd Nevins W. , Atamas Sergei P. , Arnett Heather A. 
Published: April 2014

Abstract
Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and the modulation of extracellular matrix. In this study, we demonstrate that OSM is up-regulated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and scleroderma, and investigate the pathological consequences of excess OSM in the lungs. Delivery of OSM to the lungs of mice results in a significant recruitment of inflammatory cells, as well as a dose-dependent increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. To better understand the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used genetically modified mice and show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils, and mast cells. We further explored the mechanisms of OSM-induced inflammation and fibrosis using both protein and genomic array approaches, generating a “fibrotic footprint” for OSM that shows modulation of various matrix metalloproteinases, extracellular matrix components, and cytokines previously implicated in fibrosis. In particular, although the IL-4/IL-13 and TGF-β pathways have been shown to be important and intertwined of fibrosis, we show that OSM is capable of inducing lung fibrosis independently of these pathways. The demonstration that OSM is a potent mediator of lung inflammation and extracellular matrix accumulation, combined with the up-regulation observed in patients with pulmonary fibrosis, may provide a rationale for therapeutically targeting OSM in human disease.
Fibrillar Amyloid-β Peptides Activate Microglia via TLR2: Implications for Alzheimer’s Disease
Authors: Jana Malabendu , Palencia Carlos A. , Pahan Kalipada 
Published: April 2014

Abstract
Microglial activation is an important pathological component in brains of patients with Alzheimer’s disease (AD), and fibrillar amyloid-β (Aβ) peptides play an important role in microglial activation in AD. However, mechanisms by which Aβ peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Aβ peptide-induced activation of microglia. Fibrillar Aβ1–42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Aβ1–42-induced expression of proinflammatory molecules and integrin markers in microglia. Aβ1–42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2−/− mice. Finally, the inability of Aβ1–42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2−/− mice highlights the importance of TLR2 in Aβ-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Aβ1–42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Aβ peptide-induced activation of microglia.
TGF-β1 Attenuates Mediator Release and De Novo Kit Expression by Human Skin Mast Cells through a Smad-Dependent Pathway
Authors: Zhao Wei , Gomez Gregorio , Yu Shao-Hua , Ryan John J. , Schwartz Lawrence B. 
Published: April 2014

Abstract
TGF-β has pleiotropic effects on many cell types at different stages of their development, including mast cells. The present study examines the effects of TGF-β on human skin mast cells of the MCTC type. The expression of TGF-β receptors (TGF-R) was verified at the mRNA and protein levels for TGF-RI and TGF-RII, and at the mRNA level for accessory molecules β-glycan and endoglin. TGF-β did not affect mast cell viability after 1 wk at concentrations ≤10 ng/ml, but at 50 ng/ml caused significant cell death. TGF-β inhibited surface and total expression of Kit in a dose-dependent manner, whereas the surface expression of FcεRI, FcγRI, and FcγRII was not affected. TGF-β inhibited degranulation and cytokine production, but not PGD2 production. TGF-β diminished surface Kit expression through a TGF-RI kinase/Smad-dependent pathway by inhibiting new synthesis of Kit protein, which became evident following internalization and degradation of Kit after mast cells were exposed to the Kit ligand, stem cell factor. In contrast, addition of TGF-β had no discernible effect on surface Kit expression when administered 3 days after stem cell factor, by which time surface Kit levels had returned to baseline. Although both transcription and translation are important for de novo expression of Kit, Kit mRNA levels were not affected by TGF-β. Therefore, transcription of a gene other than Kit might be involved in Kit expression. Finally, activation of mast cells increased their susceptibility to TGF-β-mediated apoptosis, a process that might regulate the survival of activated mast cells in vivo.
NF-κB-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury
Authors: Khorooshi Reza , Babcock Alicia A. , Owens Trevor 
Published: April 2014

AbstractTissue response to injury includes expression of genes encoding cytokines and chemokines. These regulate entry of immune cells to the injured tissue. The synthesis of many cytokines and chemokines involves NF-κB and signal transducers and activators of transcription (STAT). Injury to the CNS induces glial response. Astrocytes are the major glial population in the CNS. We examined expression of STATs and the chemokine CCL2 and their relationship to astroglial NF-κB signaling in the CNS following axonal transection. Double labeling with Mac-1/CD11b and glial fibrillary acidic protein revealed that STAT2 up-regulation and phosphorylation colocalized exclusively to astrocytes, suggesting the involvement of STAT2 activating signals selectively in astroglial response to injury. STAT1 was also up-regulated and phosphorylated but not exclusively in astrocytes. Both STAT2 up-regulation and phosphorylation were NF-κB -dependent since they did not occur in the lesion-reactive hippocampus of transgenic mice with specific inhibition of NF-κB activation in astrocytes. We further showed that lack of NF-κB signaling significantly reduced injury-induced CCL2 expression as well as leukocyte infiltration. Our results suggest that NF-κB signaling in astrocytes controls expression of both STAT2 and CCL2, and thus regulates infiltration of leukocytes into lesion-reactive hippocampus after axonal injury. Taken together, these findings indicate a central role for astrocytes in directing immune-glial interaction in the CNS injury response.
The Effect of the JNK Inhibitor, JIP Peptide, on Human T Lymphocyte Proliferation and Cytokine Production
Authors: Melino Michelle , Hii Charles S. , McColl Shaun R. , Ferrante Antonio 
Published: April 2014

AbstractAlthough JNK is a potential target for treating chronic inflammatory diseases, its role in T lymphocyte function remains controversial. To overcome some of the previous limitations in addressing this issue we have used the recently described transactivator of transcription-JNK-interacting protein (TAT-JIP) peptide, a specific inhibitor that was derived from the minimal JNK-binding region of the scaffold protein, JNK-interacting protein 1 (JIP-1), coupled to the short cell-permeable HIV TAT sequence. Pretreatment of purified human T lymphocytes with the TAT-JIP peptide inhibited the phosphorylation of endogenous jun activated by PHA-PMA. This was associated with a corresponding inhibition of lymphoproliferation, and of IL-2, IFN-γ, lymphotoxin, and IL-10 cytokine production. Similar results were also found using mouse splenic T cells. Examination of the specificity of TAT-JIP revealed that although the peptide was more selective than the pharmacological inhibitor, SP600125, it also inhibited cyclin-dependent kinase 2, p70 ribosomal protein S6 kinase, and serum and glucocorticoid-regulated kinase activity. Nevertheless, these data demonstrate for the first time the ability of the TAT-JIP peptide to inhibit the JNK pathway and the phosphorylation of jun in intact cells, thereby preventing the activation of the transcription factor, AP-1, and the production of Th1 and Th2 cytokines. Thus JNK could potentially be a target for the development of drugs for the treatment of autoimmune inflammatory diseases.
Active Caspase-1-Mediated Secretion of Retinoic Acid Inducible Gene-I
Authors: Kim Min-Jung , Yoo Joo-Yeon 
Published: April 2014

Abstract
Caspase-1 is an inflammatory caspase that controls the activation and secretion of the inflammatory cytokines, IL-1β and IL-18. We observed that cellular levels of retinoic acid-inducible gene-I (RIG-I) were enhanced when the pan-caspase inhibitor Z-VAD-fmk or caspase-1-specific inhibitor Z-WEHD-fmk blocked caspase activity. Overexpression of caspase-1 reduced cellular levels of RIG-I and inhibited RIG-I-mediated signaling activity. Enzymatic activity of caspase-1 was necessary to control RIG-I, although it was not a substrate of proteolytic cleavage by caspase-1. Caspase-1 physically interacted with full length RIG-I, but not with mutant forms lacking either the amino- or carboxyl-terminal domains. RIG-I was present in the supernatant of cells transfected with active caspase-1 but not with caspase-4. Stimulating cells with LPS and ATP also induced secretion of endogenous RIG-I in macrophages. Our data suggest a novel mechanism that negatively regulates RIG-I-mediated signaling activity via caspase-1-dependent secretion of RIG-I protein.
Oncostatin M-Induced and Constitutive Activation of the JAK2/STAT5/CIS Pathway Suppresses CCL1, but Not CCL7 and CCL8, Chemokine Expression
Authors: Hintzen Christoph , Haan Claude , Tuckermann Jan P. , Heinrich Peter C. , Hermanns Heike M. 
Published: April 2014

Abstract
The recruitment of leukocytes to injured tissue is crucial for the initiation of inflammatory responses as well as for immune surveillance to fight tumor progression. In this study, we show that oncostatin M, a member of the IL-6-type cytokine family and potent proinflammatory cytokine stimulates the expression of the chemokines CCL1, CCL7, and CCL8 in primary human dermal fibroblasts at a faster kinetic than IL-1β or TNF-α. The production of CCL1 and CCL8 is important for migration of monocytes, while specific Abs against CCL1 additionally inhibit the migration of T lymphocytes. We identify the mitogen-activated protein kinases ERK1/2 and p38 as crucial factors for the enhanced expression of CCL1 and CCL8. Depletion of the ERK1/2 target genes c-Jun or c-Fos strongly decrease CCL1 and CCL8 expression, while p38 MAPK prolongs the half-life of CCL1, CCL7, and CCL8 mRNA through inhibition of tristetraprolin. None of the STAT transcription factors STAT1, STAT3, or STAT5 stimulate transcription of CCL1 or CCL8. However, we identify a negative regulatory function of activated STAT5 for the gene expression of CCL1. Importantly, not STAT5 itself, but its target gene cytokine inducible SH2-domain containing protein is required for the STAT5 inhibitory effect on CCL1 expression. Finally, we show that constitutive activation of STAT5 through a mutated form of JAK2 (JAK2 V617F) occurring in patients with myeloproliferative disorders similarly suppresses CCL1 expression. Taken together, we identify novel important inflammatory target genes of OSM which are independent of STAT signaling per se, but depend on MAPK activation and are partly repressed through STAT5-dependent expression of cytokine inducible SH2-domain containing protein.
Measles Virus Infection in Adults Induces Production of IL-10 and Is Associated with Increased CD4+CD25+ Regulatory T Cells
Authors: Yu Xue-lian , Cheng Yu-ming , Shi Bi-sheng , Qian Fang-xing , Wang Feng-bin , Liu Xi-nian , Yang Hai-ying , Xu Qing-nian , Qi Tang-kai , Zha Li-jun , Yuan Zheng-hong , Ghildyal Reena 
Published: April 2014

Abstract
Despite steady progress in elimination of measles virus globally, measles infection still causes 500,000 annual deaths, mostly in developing countries where endemic measles strains still circulate. Many adults are infected every year in China, with symptoms more severe than those observed in children. In this study, we have used blood samples from adult measles patients in Shanghai and age-matched healthy controls to gain an understanding of the immune status of adult measles patients. IFN-α mRNA was reduced in patient PBMC compared with healthy controls. In contrast, gene expression and plasma production of IL-2, IL-10, and IFN-γ were elevated in patient blood. A similar cytokine profile was observed at early times when cultured PBMC were infected with a clinical isolate of measles virus. In contrast to previous studies in pediatric patients, we did not find a reduction in total CD4+ and CD8+ T cells in patient PBMC. Interestingly, we found that CD4+CD25+CD127low regulatory T cells were significantly increased in patient PBMC compared with controls. Using intracellular cytokine staining we also show that the measles virus induces IL-10-producing CD14+ and CD4+CD25+ cells in PBMC. Our results show that adult measles patients in the acute phase of the disease have a mixed Th1/Th2 type response, accompanied with severe immunosuppression of both innate and adaptive responses including suppression of type I IFN. Both regulatory T cells and plasma IL-10 may contribute to the immunosuppression.
Sunlight Triggers Cutaneous Lupus through a CSF-1-Dependent Mechanism in MRL-Fas
lpr Mice
Authors: Menke Julia , Hsu Mei-Yu , Byrne Katelyn T. , Lucas Julie A. , Rabacal Whitney A. , Croker Byron P. , Zong Xiao-Hua , Stanley E. Richard , Kelley Vicki R. 
Published: April 2014

Abstract
Sunlight (UVB) triggers cutaneous lupus erythematosus (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø)-mediated mechanism in MRL-Faslpr mice. By constructing mutant MRL-Faslpr strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex vivo gene transfer to deliver CSF-1 intradermally, we determined that CSF-1 induces CLE in lupus-susceptible MRL-Faslpr mice, but not in lupus-resistant BALB/c mice. UVB incites an increase in Møs, apoptosis in the skin, and CLE in MRL-Faslpr, but not in CSF-1-deficient MRL-Faslpr mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Møs that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Faslpr but not lupus-resistant BALB/c mice. Taken together, CSF-1 is envisioned as the match and lupus susceptibility as the tinder leading to CLE.
Cutting Edge: CD4+ T Cell-Derived IL-2 Is Essential for Help-Dependent Primary CD8+ T Cell Responses
Authors: Wilson Elizabeth B. , Livingstone Alexandra M. 
Published: April 2014

Abstract
CD4+ T cell help is essential for primary CD8+ T cell responses to noninflammatory Ags. IL-2 is one of the principal cytokines made by naive CD4+ T cells, and we show in this study that it is an essential component of help. Adoptively transferred naive CD4+ TCR-transgenic OT-II cells supported endogenous primary CD8+ T cell responses, but IL-2-deficient OT-II cells were unable to provide help, although they responded to Ag in vivo and up-regulated CD40 ligand in vitro. Wild -type OT-II cells helped endogenous CD8+ T cell responses in IL-2-deficient mice, but not in IL-2Rα-deficient mice. Thus, CD4+ T cell-derived IL-2 is essential for CD8+ T cell responses to noninflammatory, cell-associated Ags. We suggest that it is also a critical component of help for CD8+ T cell responses to pathogens, because protective memory also requires CD8+ T cell stimulation by IL-2 during priming.
Requirement of IL-17RA in Con A Induced Hepatitis and Negative Regulation of IL-17 Production in Mouse T Cells
Authors: Nagata Takako , Mckinley Laura , Peschon Jacques J. , Alcorn John F. , Aujla Shean J. , Kolls Jay K. 
Published: April 2014

Abstract
Th17 cells, a subset of T cells involved in autoimmunity and host defense against extracellular Gram-negative infection, express both IL-17A and IL-17F. Both IL-17A and IL-17F can signal via the IL-17RA; however, IL-17F does so at a 1- to 2-log higher concentration than IL-17A. In this study, we show that the IL-17F homodimer via IL-17RA is a negative regulator of IL-17 production in T cells and suggest a mechanism whereby IL-17RA on T cells serves as an autocrine/paracrine regulator of IL-17 synthesis in T cells.
Lin−Sca1+Kit− Bone Marrow Cells Contain Early Lymphoid-Committed Precursors That Are Distinct from Common Lymphoid Progenitors
Authors: Kumar Ritu , Fossati Valentina , Israel Mason , Snoeck Hans-Willem 
Published: April 2014

Abstract
The significance of a population in mouse bone marrow of lineage-negative (Lin−), Sca1-positive, c-kit-negative (LSK−) cells, which is reported to be devoid of long-term repopulation capacity or myeloid potential, is unknown. In this study, we show that the LSK− population is composed of several subsets defined by the expression of flt3, CD25, and IL-7Rα. The first subset was CD25− and more than 90% expressed either flt3, IL-7Rα, or both. The CD25−LSK− population had T cell, B cell, and NK cell potential in vivo, and most of this activity was localized in the flt3+ subset, irrespective of the expression of IL-7Rα. Although lymphoid potential of flt3+LSK− cells in vivo was 3-fold lower than that of lin−Sca1lowkitlowIL7Rα+ common lymphoid progenitors (CLPs), their cloning efficiency in vitro was 10-fold lower than that of CLPs. Furthermore, although the myeloid potential of flt3+LSK− cells was 10-fold lower than that of CLPs in the absence of M-CSF, the relative myeloid potential of both populations was similar in its presence. These observations suggest differential growth factor requirements of both populations. The second subset of LSK− cells was homogeneously CD25+flt3−IL7Rα+ and could be generated from both CD25−LSK− cells and from CLPs, but did not engraft in immunodeficient Rag1−/− or Rag1−/−γc−/− hosts. This population, of which the significance is unclear, was increased in Rag1−/− mice and in old mice. Thus, the LSK− population is phenotypically and functionally heterogeneous and contains early lymphoid-committed precursors. Our findings imply that the early stages of lymphoid commitment are more complex than was thus far assumed.
Deregulation of c-Myc Confers Distinct Survival Requirements for Memory B Cells, Plasma Cells, and Their Progenitors
Authors: Khuda Sefat E. , Loo William M. , Janz Siegfried , Van Ness Brian , Erickson Loren D. 
Published: April 2014

Abstract
Deregulation of the c-Myc oncogene is tightly associated with human and murine plasma cell (PC) neoplasms. Through the analysis of Ag-specific B cell responses in mice where Myc is targeted to the Igh Cα locus, we show here that c-Myc dramatically impairs the primary and secondary Ab response. This impairment is differentiation stage specific, since germinal center B cell formation, affinity maturation, and class switch recombination were intact. Examination of PC viability revealed that c-Myc triggered apoptosis only upon final maturation when Ab is secreted and is resistant to the survival factor BAFF (B cell-activating factor belonging to the TNF family). In contrast, PC precursors (PCpre) that ultimately give rise to mature PCs survived normally and vigorously expanded with BAFF signaling. We further show that c-Myc also facilitates the apoptosis of memory B cells. Thus, Cα-Myc controls both cellular arms of long-lived B cell immunity than previously anticipated. Only when deregulation of c-Myc was combined with enforced Bcl-xL expression were mature PCs able to survive in response to BAFF. These data indicate that the survival requirements for tumor-susceptible PCpre and PCs are distinct and that tumor progression likely develops as PCpre transition to functional PCs when apoptotic pathways such as members of the Bcl-2 family are disabled.