bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Resistance of Restraint-Stressed Mice to Sepsis
Authors: Wang Yu , Lu Ying , Yu Duo , Wang Yongqiang , Chen Fuyong , Yang Hanchun , Zheng Shijun J. 
Published: April 2014

Abstract
Sepsis remains a major health concern across the world. The effects of stress on host resistance to sepsis are still not very clear. To explore the effects of chronic stress on sepsis’ we examined the impact of restraint stress on the resistance of mice to sepsis. Interestingly, it was found that restraint stress enhanced the antisepsis resistance of mice and the concentrations of the proinflammatory cytokines IL-1, IL-6, IL-12, and TNF-α in the blood of stressed mice were dramatically reduced post Escherichia coli infection or LPS treatment as compared with that of controls (p &lt; 0.05). In addition, the mRNA expressions of glucocorticoid-induced leucine zipper (GILZ) were up-regulated in the spleen and peritoneal macrophages of mice receiving restraint stress or dexamethasone treatment. These results demonstrate that restraint stress enhances the resistance of mice to sepsis, supporting corticotherapy for sepsis and proposing restraint-stressed mouse as an animal model to elucidate mechanisms of stress-associated, antisepsis resistance.
IL-17A Produced by γδ T Cells Plays a Critical Role in Innate Immunity against Listeria monocytogenes Infection in the Liver
Authors: Hamada Satoru , Umemura Masayuki , Shiono Takeru , Tanaka Kensho , Yahagi Ayano , Begum M. Dilara , Oshiro Kiyotetsu , Okamoto Yuko , Watanabe Hisami , Kawakami Kazuyoshi , Roark Christina , Born Willi K. , O'Brien Rebecca , Ikuta Koichi , Ishikawa Hiromichi , Nakae Susumu , Iwakura Yoichiro , Ohta Takao , Matsuzaki Goro 
Published: April 2014

Abstract
IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4+ Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR γδ T cells expressing TCR Vγ4 or Vγ6. Interestingly, TCR γδ T cells expressing both IFN-γ and IL-17A were hardly detected, indicating that the IL-17A-producing TCR γδ T cells are distinct from IFN-γ-producing γδ T cells, similar to the distinction between Th17 and Th1 in CD4+ T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR γδ T cells, which is important in innate immunity in the liver.
TLR Adaptor MyD88 Is Essential for Pathogen Control during OralToxoplasma gondiiInfection but Not Adaptive Immunity Induced by a Vaccine Strain of the Parasite
Authors: Sukhumavasi Woraporn , Egan Charlotte E. , Warren Amy L. , Taylor Gregory A. , Fox Barbara A. , Bzik David J. , Denkers Eric Y. 
Published: April 2014

AbstractTLR adaptor MyD88 activation is important in host resistance to Toxoplasma gondii during i.p. infection, but the function of this signaling pathway during oral infection, in which mucosal immunity assumes a predominant role, has not been examined. In this study, we show that MyD88−/− mice fail to control the parasite and succumb within 2 wk of oral infection. Early during infection, T cell IFN-γ production, recruitment of neutrophils and induction of p47 GTPase IGTP (Irgm3) in the intestinal mucosa were dependent upon functional MyD88. Unexpectedly, these responses were MyD88-independent later during acute infection. In particular, CD4+ T cell IFN-γ reached normal levels independently of MyD88, despite continued absence of IL-12 in these animals. The i.p. vaccination of MyD88−/− mice with an avirulent T. gondii uracil auxotroph elicited robust IFN-γ responses and protective immunity to challenge with a high virulence T. gondii strain. Our results demonstrate that MyD88 is required to control Toxoplasma infection, but that the parasite can trigger adaptive immunity without the need for this TLR adaptor molecule.
Lipopolysaccharide Is a Direct Agonist for Platelet RNA Splicing
Authors: Shashkin Pavel N. , Brown G. Thomas , Ghosh Arundhati , Marathe Gopal K. , McIntyre Thomas M. 
Published: April 2014

Abstract
Platelets express TLR4 receptors, but its ligand LPS does not directly activate thrombotic functions nor, obviously, transcription by these anucleate cells. Platelets, however, store information that changes their phenotype over a few hours in the form of unprocessed RNA transcripts. We show even low concentrations of LPS in the presence of soluble CD14 initiated splicing of unprocessed IL-1β RNA, with translation and accumulation of IL-1β protein. LPS was a more robust agonist for this response than thrombin. Platelets also contained cyclooxygenase-2 pre-mRNA, which also was spliced and translated after LPS stimulation. Flow cytometry and immunocytochemistry of platelets extensively purified by negative immunodepletion showed platelets contained IL-1β, and quantitative assessment of white blood cell contamination by CD14 real time PCR confirms that leukocytes were not the IL-1β source, nor were they required for platelet stimulation. LPS did not initiate rapid platelet responses, but over time did prime platelet aggregation to soluble agonists, induced actin rearrangement, and initiated granule secretion with P-selectin expression that resulted the coating of quiescent leukocytes with activated platelets. LPS is a direct agonist for platelets that allows these cells to directly participate in the innate immune response to bacteria.
Phosphorylation of 5-Lipoxygenase at Ser523 by Protein Kinase A Determines Whether Pioglitazone and Atorvastatin Induce Proinflammatory Leukotriene B4 or Anti-Inflammatory 15-Epi-Lipoxin A4 Production
Authors: Ye Yumei , Lin Yu , Perez-Polo Jose R. , Uretsky Barry F. , Ye Zaiming , Tieu Brian C. , Birnbaum Yochai 
Published: April 2014

Abstract
The 5-lipoxygenase (5LO) produces leukotriene B4 and 15-epilipoxin-A4 (15-epi-LXA4). Phosphorylation at Ser523 by protein kinase A (PKA) prevents 5LO shift to the perinuclear membrane. Atorvastatin and pioglitazone up-regulate 15-epi-LXA4 production in the heart. We assessed whether phosphorylation of 5LO by PKA determines whether 5LO interacts with the membranous cytosolic phospholipase A2 (cPLA2) to produce leukotriene B4 or with cyclooxygenase-2 (COX2) to produce 15-epi-LXA4. Rats received either pioglitazone, atorvastatin, pioglitazone plus atorvastatin, vehicle, or LPS. Rat myocardial cells were incubated with pioglitazone plus atorvastatin, pioglitazone plus atorvastatin plus H-89 (PKA inhibitor), H-89, or vehicle for 8 h. Pioglitazone and atorvastatin did not affect total 5LO expression. However, both increased 5LO levels in the cytosolic fraction. H-89 caused a shift of 5LO to the membranous fraction in atorvastatin- and pioglitazone-treated rats. Pioglitazone and atorvastatin increased phospho-5LO levels. H-89 attenuated this increase. Both pioglitazone and atorvastatin increased COX2 levels in the cytosolic fraction and the membranous fraction. H-89 prevented this increase. Pioglitazone and atorvastatin increased cPLA2 expression in the membranous fraction. This effect was not attenuated by H-89. Pioglitazone plus atorvastatin increased 15-epi-LXA4 levels. H-89 attenuated the effect of pioglitazone plus atorvastatin. Pioglitazone plus atorvastatin plus H-89 increased leukotriene B4 levels. Coimmunoprecipitation showed that without H-89, atorvastatin and pioglitazone induced an interaction between 5LO and COX2 in the cytosolic fraction, whereas when H-89 was added, 5LO interacted with cPLA2 on the membranous fraction. The 5LO phosphorylation determines whether 15-epi-LXA4 (anti-inflammatory) or leukotriene B4 (inflammatory mediator) is produced.
Mitochondrial Structural Changes and Dysfunction Are Associated with Experimental Allergic Asthma
Authors: Mabalirajan Ulaganathan , Dinda Amit Kumar , Kumar Sarvesh , Roshan Reema , Gupta Pooja , Sharma Surendra Kumar , Ghosh Balaram 
Published: April 2014

Abstract
An imbalance between Th1 and Th2 immune response is crucial for the development of pathophysiological features of asthma. A Th2-dominant response produces oxidative stress in the airways, and it is thought to be one of the crucial components of asthma pathogenesis. Although mitochondrion is a crucial organelle to produce endogenous reactive oxygen species, its involvement in this process remains unexplored as yet. We demonstrate in this study that OVA-induced experimental allergic asthma in BALB/c mice is associated with mitochondrial dysfunction, such as reduction of cytochrome c oxidase activity in lung mitochondria, reduction in the expression of subunit III of cytochrome c oxidase in bronchial epithelium, appearance of cytochrome c in the lung cytosol, decreased lung ATP levels, reduction in the expression of 17 kDa of complex I in bronchial epithelium, and mitochondrial ultrastructural changes such as loss of cristae and swelling. However, there was no change in the expression of subunits II and III of cytochrome c oxidase. Interestingly, administration of IL-4 mAb reversed these mitochondrial dysfunction and structural changes. In contrast, IFN-γ mAb administration neither reversed nor further deteriorated the mitochondrial dysfunction and structural changes compared with control asthmatic mice administered with isotypic control Ab, although airway hyperresponsiveness deteriorated further. These results suggest that mitochondrial structural changes and dysfunction are associated with allergic asthma. These findings may help in the development of novel drug molecules targeting mitochondria for the treatment of asthma.
Tissue-Type Plasminogen Activator Is a Regulator of Monocyte Diapedesis through the Brain Endothelial Barrier
Authors: Reijerkerk Arie , Kooij Gijs , van der Pol Susanne M. A. , Leyen Thomas , van het Hof Bert , Couraud Pierre-Olivier , Vivien Denis , Dijkstra Christine D. , de Vries Helga E. 
Published: April 2014

Abstract
Inflammatory cell trafficking into the brain complicates several neurological disorders including multiple sclerosis. Normally, reliable brain functioning is maintained and controlled by the blood-brain barrier (BBB), which is essential to restrict the entry of potentially harmful molecules and cells from the blood into the brain. The BBB is a selective barrier formed by dedicated brain endothelial cells and dependent on the presence of intracellular tight junctions. In multiple sclerosis, a severe dysfunction of the BBB is observed, which is key to monocyte infiltration and inflammation in the brain. Proteolytic activity has been associated with these inflammatory processes in the brain. Our studies in plasma of rats indicated that the extracellular protease tissue-type plasminogen activator (tPA) correlates with the clinical signs of experimental allergic encephalomyelitis, a rat model of multiple sclerosis. In this study, we studied the function of the tPA during diapedesis of monocytes through a rat and human brain endothelial barrier. Monocyte-brain endothelial cell coculture experiments showed that monocytes induce the release of tPA by brain endothelial cells, which subsequently activates the signal transduction protein extracellular signal related kinase (ERK1/2), both involved in monocyte diapedesis. Importantly, live imaging and immunoblot analyses of rat brain endothelial cells revealed that tPA and ERK1/2 control the breakdown of the tight junction protein occludin. These studies identify tPA as a novel and relevant pathological mediator of neuroinflammation and provide a potential mechanism for this.
Transcriptional and Translational Regulation of TGF-β Production in Response to Apoptotic Cells
Authors: Xiao Yi Qun , Freire-de-Lima Celio G. , Schiemann William P. , Bratton Donna L. , Vandivier R. William , Henson Peter M. 
Published: April 2014

Abstract
Interaction between apoptotic cells and phagocytes through phosphatidylserine recognition structures results in the production of TGF-β, which has been shown to play pivotal roles in the anti-inflammatory and anti-immunogenic responses to apoptotic cell clearance. Using 3T3-TβRII and RAWTβRII cells in which a truncated dominant-negative TGF-β receptor II was stably transfected to avoid autofeedback induction of TGF-β, we investigate the mechanisms by which TGF-β was produced through PSRS engagement. We show, in the present study, that TGF-β was regulated at both transcriptional and translational steps. P38 MAPK, ERK, and JNK were involved in TGF-β transcription, whereas translation required activation of Rho GTPase, PI3K, Akt, and mammalian target of rapamycin with subsequent phosphorylation of translation initiation factor eukaryotic initiation factor 4E. Strikingly, these induction pathways for TGF-β production were different from those initiated in the same cells responding to LPS or PMA.
Myeloid-Related Proteins Rapidly Modulate Macrophage Nitric Oxide Production during Innate Immune Response
Authors: Pouliot Philippe , Plante Isabelle , Raquil Marie-Astrid , Tessier Philippe A. , Olivier Martin 
Published: April 2014

Abstract
S100A8 and S100A9 are intracellular calcium-binding proteins produced by myeloid cells that promote neutrophil/monocyte recruitment at inflamed tissues by enhancing attachment to endothelial cells. Although the intracellular functions of these proteins, i.e., myeloid-related proteins (MRP)-8 and MRP-14, are not completely understood, these proteins exhibit prominent extracellular cytokine-like functions and are considered reliable markers of inflammation in diverse diseases. As S100A8 and S100A9 have been reported to be rapidly released in response to components derived from infectious agents, we hypothesized that they play an important role in the modulation of key microbicidal phagocyte functions. In this study, we report for the first time that MRPs are powerful inducers of NO production by murine macrophages (Mφ). This increase in NO production was linked to an increased inducible NO synthase expression both at gene and protein level. This induction was concomitant with an important phosphorylation of SAPK/JNK, but also of MEK and ERK kinases. Upon stimulation with MRPs, NF-κB was rapidly translocated to the nucleus (30 min). When Mφ were treated concomitantly with IFN-γ, another activator of Mφ functions, we observed a strong synergy in NO production, synergy that resulted from the engagement of exclusive signaling pathways: SAPK/JNK, ERK and NF-κB were involved in signaling of MRPs, whereas IFN-γ uses the JAK/STAT pathway. This suggests that the synergy results from interactions of transcription factors in the promoter region. Finally, we observed this effect to be dependent on TLR4. Collectively, our study unravels the importance of MRPs as potent new inducers of Mφ NO production.
Neutrophil Apoptosis: Selective Regulation by Different Ligands of Integrin αMβ2
Authors: Pluskota Elzbieta , Soloviev Dmitry A. , Szpak Dorota , Weber Christian , Plow Edward F. 
Published: April 2014

Abstract
Neutrophils undergo spontaneous apoptosis, but their survival can be extended during inflammatory responses. αMβ2 is reported either to delay or accelerate neutrophil apoptosis, but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood. The abilities of closely related αMβ2 ligands, plasminogen and angiostatin, derived from plasminogen, as well as fibrinogen and its two derivative αMβ2 recognition peptides, P1 and P2-C, differed markedly in their effects on neutrophil apoptosis. Plasminogen, fibrinogen, and P2-C suppressed apoptosis via activation of Akt and ERK1/2 kinases, while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis. Using cells transfected with αMβ2 or its individual αM or β2 subunits, and purified receptors and its constituent chains, we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response. Hence, engagement of a single integrin by closely related ligands can induce distinct signaling pathways, which can elicit distinct cellular responses.
Nucleotide Oligomerization Domains 1 and 2: Regulation of Expression and Function in Preadipocytes
Authors: Stroh Thorsten , Batra Arvind , Glauben Rainer , Fedke Inka , Erben Ulrike , Kroesen Anjo , Heimesaat Markus M. , Bereswill Stefan , Girardin Stephen , Zeitz Martin , Siegmund Britta 
Published: April 2014

Abstract
Translocation of bacteria into the mesenteric fat during intestinal inflammation and the expression of functional TLR1–9 in murine preadipocytes and adipocytes suggest an active role for these cells in innate immunity. The present study focuses on nucleotide oligomerization domains 1 and 2 representing intracellular pattern recognition receptors that sense motifs derived from bacterial peptidoglycans. On mRNA level nucleotide oligomerization domain 1 was found to be constitutively expressed in the preadipocyte cell line 3T3L1 and in primary preadipocytes isolated from murine mesenteric fat, while nucleotide oligomerization domain 2 was only weakly expressed by these cells. Treatment with lactyl-tetra-diaminopimelic acid, muramyl dipeptide, LPS, IL-1β, and TNF-α did not affect cellular nucleotide oligomerization domain 1 mRNA amounts. Except muramyl dipeptide, all factors significantly increased nucleotide oligomerization domain 2 mRNA in mesenteric fat preadipocytes after 4 h. However, specific stimulation of nucleotide oligomerization domain 1 induced IL-6 synthesis in preadipocytes from wild-type or TLR2/4-deficient mice. Confirming nucleotide oligomerization domain 1 specificity, transfection of nucleotide oligomerization domain 1-specific small interfering RNA significantly blocked the effect of lactyl-tetra-diaminopimelic acid on IL-6 production. With specific inhibitors and a NF-κB reporter plasmid, nucleotide oligomerization domain 1-mediated activation of NF-κB was shown to be responsible for the induction of IL-6 in preadipocytes. In addition, expression of functional nucleotide oligomerization domain 1 could be confirmed in primary human preadipocytes. In summary, we here identified preadipocytes as a novel cell population expressing nucleotide oligomerization domains 1 and 2. Not regulated on transcriptional level, nucleotide oligomerization domain 1 in preadipocytes serves as a sensor for bacterial degradation products and triggers proinflammatory effector responses. Thus, our results further strengthen the allocation of the mesenteric fat and especially of preadipocytes to the innate immune system.
CD43 Plays Both Antiadhesive and Proadhesive Roles in Neutrophil Rolling in a Context-Dependent Manner
Authors: Matsumoto Masanori , Shigeta Akiko , Miyasaka Masayuki , Hirata Takako 
Published: April 2014

Abstract
As the first step in the recruitment of neutrophils into tissues, the cells become tethered to and roll on the vessel wall. These processes are mediated by interactions between the P- and E-selectins, expressed on the endothelial cells of the vessel wall, and their ligands, expressed on the neutrophils. Recently, we reported that CD43 on activated T cells functions as an E-selectin ligand and thereby mediates T cell migration to inflamed sites, in collaboration with P-selectin glycoprotein ligand-1 (PSGL-1), a major P- and E-selectin ligand. Here, we examined whether CD43 on neutrophils also functions as an E-selectin ligand. CD43 was precipitated with an E-selectin-IgG chimera from mouse bone marrow neutrophils. A CD43 deficiency diminished the E-selectin-binding activity of neutrophils when PSGL-1 was also deficient. Intravital microscopy showed that the CD43 deficiency significantly increased leukocyte rolling velocities in TNF-α-stimulated venules blocked with an anti-P-selectin mAb, where the rolling was mostly E-selectin dependent, when PSGL-1 was also absent. In contrast, in venules with trauma-induced inflammation, where the rolling was largely P-selectin dependent, the CD43 deficiency reduced leukocyte rolling velocities. Collectively, these observations suggest that CD43 generally serves as an antiadhesive molecule to attenuate neutrophil-endothelial interactions, but when E-selectin is expressed on endothelial cells, it also plays a proadhesive role as an E-selectin ligand.
Potent Simian Immunodeficiency Virus-Specific Cellular Immune Responses in the Breast Milk of Simian Immunodeficiency Virus-Infected, Lactating Rhesus Monkeys
Authors: Permar Sallie R. , Kang Helen H. , Carville Angela , Mansfield Keith G. , Gelman Rebecca S. , Rao Srinivas S. , Whitney James B. , Letvin Norman L. 
Published: April 2014

Abstract
Breast milk transmission of HIV is a leading cause of infant HIV/AIDS in the developing world. Remarkably, only a small minority of breastfeeding infants born to HIV-infected mothers contract HIV via breast milk exposure, raising the possibility that immune factors in the breast milk confer protection to the infants who remain uninfected. To model HIV-specific immunity in breast milk, lactation was pharmacologically induced in Mamu-A*01+ female rhesus monkeys. The composition of lymphocyte subsets in hormone-induced lactation breast milk was found to be similar to that in natural lactation breast milk. Hormone-induced lactating monkeys were inoculated i.v. with SIVmac251 and CD8+ T lymphocytes specific for two immunodominant SIV epitopes, Gag p11C and Tat TL8, and SIV viral load were monitored in peripheral blood and breast milk during acute infection. The breast milk viral load was 1–2 logs lower than plasma viral load through peak and set point of viremia. Surprisingly, whereas the kinetics of the SIV-specific cellular immunity in breast milk mirrored that of the blood, the peak magnitude of the SIV-specific CD8+ T lymphocyte response in breast milk was more than twice as high as the cellular immune response in the blood. Furthermore, the appearance of the SIV-specific CD8+ T lymphocyte response in breast milk was associated with a reduction in breast milk viral load, and this response remained higher than that in the blood after viral set point. This robust viral-specific cellular immune response in breast milk may contribute to control of breast milk virus replication.
Chronic Lymphocytic Leukemia Cells Bind and Present the Erythrocyte Protein Band 3: Possible Role as Initiators of Autoimmune Hemolytic Anemia
Authors: Galletti Jeremías , Cañones Cristian , Morande Pablo , Borge Mercedes , Oppezzo Pablo , Geffner Jorge , Bezares Raimundo , Gamberale Romina , Giordano Mirta 
Published: April 2014

Abstract
The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4+ T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.