bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse and Potent Chemokine Production by Lung CD11bhigh Dendritic Cells in Homeostasis and in Allergic Lung Inflammation
Authors: Beaty Steven R. , Rose C. Edward , Sung Sun-sang J. 
Published: April 2014

AbstractLung CD11chigh dendritic cells (DC) are comprised of two major phenotypically distinct populations, the CD11bhigh DC and the integrin αEβ7+ DC (CD103+ DC). To examine whether they are functionally distinguishable, global microarray studies and real-time PCR analysis were performed. Significant differences between the two major CD11chigh DC types in chemokine mRNA expression were found. CD11bhigh DC is a major secretory cell type and highly expressed at least 16 chemokine mRNA in the homeostatic state, whereas CD103+ DC highly expressed only 6. Intracellular chemokine staining of CD11chigh lung cells including macrophages, and ELISA determination of sort-purified CD11chigh cell culture supernatants, further showed that CD11bhigh DC produced the highest levels of 9 of 14 and 5 of 7 chemokines studied, respectively. Upon LPS stimulation in vitro and in vivo, CD11bhigh DC remained the highest producer of 7 of 10 of the most highly produced chemokines. Induction of airway hyperreactivity and lung inflammation increased lung CD11bhigh DC numbers markedly, and they produced comparable or higher amounts of 11 of 12 major chemokines when compared with macrophages. Although not a major producer, CD103+ DC produced the highest amounts of the Th2-stimulating chemokines CCL17/thymus and activation-related chemokine and CCL22/monocyte-derived chemokine in both homeostasis and inflammation. Significantly, CCL22/monocyte-derived chemokine exhibited regulatory effects on CD4+ T cell proliferation. Further functional analysis showed that both DC types induced comparable Th subset development. These studies showed that lung CD11bhigh DC is one of the most important leukocyte types in chemokine production and it is readily distinguishable from CD103+ DC in this secretory function.
Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia
Authors: Quinton Lee J. , Jones Matthew R. , Simms Benjamin T. , Kogan Mariya S. , Robson Bryanne E. , Skerrett Shawn J. , Mizgerd Joseph P. 
Published: April 2014

Abstract
Eradication of bacteria in the lower respiratory tract depends on the coordinated expression of proinflammatory cytokines and consequent neutrophilic inflammation. To determine the roles of the NF-κB subunit RelA in facilitating these events, we infected RelA-deficient mice (generated on a TNFR1-deficient background) with Streptococcus pneumoniae. RelA deficiency decreased cytokine expression, alveolar neutrophil emigration, and lung bacterial killing. S. pneumoniae killing was also diminished in the lungs of mice expressing a dominant-negative form of IκBα in airway epithelial cells, implicating this cell type as an important locus of NF-κB activation during pneumonia. To study mechanisms of epithelial RelA activation, we stimulated a murine alveolar epithelial cell line (MLE-15) with bronchoalveolar lavage fluid (BALF) harvested from mice infected with S. pneumoniae. Pneumonic BALF, but not S. pneumoniae, induced degradation of IκBα and IκBβ and rapid nuclear accumulation of RelA. Moreover, BALF-induced RelA activity was completely abolished following combined but not individual neutralization of TNF and IL-1 signaling, suggesting either cytokine is sufficient and necessary for alveolar epithelial RelA activation during pneumonia. Our results demonstrate that RelA is essential for the host defense response to pneumococcus in the lungs and that RelA in airway epithelial cells is primarily activated by TNF and IL-1.
Increased Levels of NF-ATc2 Differentially Regulate CD154 and IL-2 Genes in T Cells from Patients with Systemic Lupus Erythematosus
Authors: Kyttaris Vasileios C. , Wang Ying , Juang Yuang-Taung , Weinstein Arthur , Tsokos George C. 
Published: April 2014

AbstractT cells from patients with systemic lupus erythematosus (SLE) are characterized by heightened TCR-initiated free intracytoplasmic calcium responses. We demonstrate that activated T cells from SLE patients, but not from rheumatoid arthritis patients, displayed higher levels of the calcineurin-dependent transcription factor NF-ATc2 in the nucleus compared with control T cells. DNA NF-AT-binding activity was also increased, as was the amount of NF-ATc2 bound to the promoters of CD154 (CD40L) and IL-2 genes. Nevertheless, although high NF-ATc2 levels translated into higher CD154 transcription in SLE, IL-2 transcription was decreased. The absence of important transcriptional activators (AP-1, NF-κΒ) and the presence of transcriptional repressors (cAMP response element modulator) on the IL-2 promoter explain this dichotomous effect.
Cutting Edge: Loss of TLR2, TLR4, and TLR5 on Langerhans Cells Abolishes Bacterial Recognition
Authors: van der Aar Angelic M.G. , Sylva-Steenland Regien M. R. , Bos Jan D. , Kapsenberg Martien L. , de Jong Esther C. , Teunissen Marcel B. M. 
Published: April 2014

Abstract
It is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broad TLR expression profile, whereas human LCs have a selective impaired expression of cell surface TLR2, TLR4, and TLR5, all involved in bacterial recognition. This distinct TLR expression profile is acquired during the TGF-β1-driven development of LCs in vitro. Consequently, and in contrast to DDCs, LCs weakly respond to bacterial TLR2, TLR4, and TLR5 ligands in terms of cytokine production and maturation, as well as to whole Gram-positive and Gram-negative bacteria, whereas their responsiveness to viral TLR ligands and viruses is fully active and comparable to DDCs. Unresponsiveness of LCs to bacteria may be a mechanism that contributes to tolerance to bacterial commensals that colonize the skin.
Non-T Cell Activation Linker (NTAL) Negatively Regulates TREM-1/DAP12-Induced Inflammatory Cytokine Production in Myeloid Cells
Authors: Tessarz Anja S. , Weiler Sandra , Zanzinger Kai , Angelisová Pavla , Horejsí Václav , Cerwenka Adelheid 
Published: April 2014

Abstract
The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-α and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12). In general, ITAM-mediated signals lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in mouse macrophages and dendritic cells. To date, signals downstream of the TREM-1 and DAP12 complex in myeloid cells are poorly defined. By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes. Using RNA interference to decrease the expression levels of NTAL, we demonstrate that in NTAL knockdown cell lines the phosphorylation of ERK1/2 is enhanced. In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca2+ after TREM-1 triggering. Most importantly, we demonstrate that NTAL acts as a negative regulator of TNF-α and IL-8 production after stimulation via TREM-1. Our results show that activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL, identifying NTAL as gatekeeper of TREM-1/DAP12-induced signaling in myeloid cells.
Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development
Authors: Falahati Rustom , Leitenberg David 
Published: April 2014

Abstract
CD45-dependent dephosphorylation of the negative regulatory C-terminal tyrosine of the Src family kinase Lck, promotes efficient TCR signal transduction. However, despite the role of CD45 in positively regulating Lck activity, the distinct phenotypes of CD45 and Lck/Fyn-deficient mice suggest that the role of CD45 in promoting Lck activity may be differentially regulated during thymocyte development. In this study, we have found that the C-terminal tyrosine of Lck (Y505) is markedly hyperphosphorylated in total thymocytes from CD45-deficient mice compared with control animals. In contrast, regulation of the Lck Y505 phosphorylation in purified, double-negative thymocytes is relatively unaffected in CD45-deficient cells. These changes in the role of CD45 in regulating Lck phosphorylation during thymocyte development correlate with changes in coreceptor expression and the presence of coreceptor-associated Lck. Biochemical analysis of coreceptor-associated and nonassociated Lck in thymocytes, and in cell lines varying in CD4 and CD45 expression, indicate that CD45-dependent regulation of Lck Y505 phosphorylation is most evident within the fraction of Lck that is coreceptor associated. In contrast, Lck Y505 phosphorylation that is not coreceptor associated is less affected by the absence of CD45. These data define distinct pools of Lck that are differentially regulated by CD45 during T cell development.
Suppression of the Effector Phase of Inflammatory Arthritis by Double-Stranded RNA Is Mediated by Type I IFNs
Authors: Yarilina Anna , DiCarlo Edward , Ivashkiv Lionel B. 
Published: April 2014

Abstract
Innate immune receptors that recognize nucleic acids, such as TLRs and RNA helicases, are potent activators of innate immunity that have been implicated in the induction and exacerbation of autoimmunity and inflammatory arthritis. Polyriboinosine-polyribocytidylic acid sodium salt (poly(IC)) is a mimic of dsRNA and viral infection that activates TLR3 and the RNA helicases retinoic acid-induced gene-1 and melanoma differentiation-associated gene-5, and strongly induces type I IFN production. We analyzed the effects of systemic delivery of poly(IC) on the inflammatory effector phase of arthritis using the collagen Ab-induced and KRN TCR-transgenic mouse serum-induced models of immune complex-mediated experimental arthritis. Surprisingly, poly(IC) suppressed arthritis, and suppression was dependent on type I IFNs that inhibited synovial cell proliferation and inflammatory cytokine production. Administration of exogenous type I IFNs was sufficient to suppress arthritis. These results suggest a regulatory role for innate immune receptors for dsRNA in modulating inflammatory arthritis and provide additional support for an anti-inflammatory function of type I IFNs in arthritis that directly contrasts with a pathogenic role in promoting autoimmunity in systemic lupus.
The Role of Endoplasmic Reticulum-Associated Aminopeptidase 1 in Immunity to Infection and in Cross-Presentation
Authors: Firat Elke , Saveanu Loredana , Aichele Peter , Staeheli Peter , Huai Jisen , Gaedicke Simone , Nil Ahmed , Besin Gilles , Kanzler Benoît , van Endert Peter , Niedermann Gabriele 
Published: April 2014

Abstract
Endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) is involved in the final processing of endogenous peptides presented by MHC class I molecules to CTLs. We generated ERAP1-deficient mice and analyzed cytotoxic responses upon infection with three viruses, including lymphocytic choriomeningitis virus, which causes vigorous T cell activation and is controlled by CTLs. Despite pronounced effects on the presentation of selected epitopes, the in vivo cytotoxic response was altered for only one of several epitopes tested. Moreover, control of lymphocytic choriomeningitis virus was not impaired in the knockout mice. Thus, we conclude that lack of ERAP1 has little influence on antiviral immunohierarchies and antiviral immunity in the infections studied. We also focused on the role of ERAP1 in cross-presentation. We demonstrate that ERAP1 is required for efficient cross-presentation of cell-associated Ag and of OVA/anti-OVA immunocomplexes. Surprisingly, however, ERAP1 deficiency has no effect on cross-presentation of soluble OVA, suggesting that for soluble exogenous proteins, final processing may not take place in an environment containing active ERAP1.
Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice
Authors: Arrode Geraldine , Hegde Ramakrishna , Mani Arunmani , Jin Yuhuai , Chebloune Yahia , Narayan Opendra 
Published: April 2014

Abstract
HIV DNA vaccines are potent inducers of cell-mediated immune (CMI) response in mice but elicit poor HIV-specific IFN-γ-producing T cells in monkeys and humans. In this study, we performed kinetic analyses on splenocytes of BALB/c mice that were immunized by a single injection with a unique DNA vaccine. Using IFN-γ-ELISPOT and multiparametric FACS analysis, we characterized the induced CMI response. We found that the response was detectable for at least 63 wk. ELISPOT detection of IFN-γ-producing T cells showed a profile with two waves separated by a long period of minimal response. Multiparametric FACS analysis showed two populations of CD3+CD8+ T cells that were specific for all HIV Ags. These cells had similar robust proliferation abilities and contained granzyme B. However, only a few produced IFN-γ. Both IFN-γ-producing and non-IFN-γ-producing HIV-specific CD8+ T cells were detected in the early stage (week (W)1 and W2 postimmunization (PI)), in the prolonged intermediate period of minimal response (W4-W26 PI), and in the final late phase of increased response (W30-W63 PI). Our longitudinal characterization showed that both subsets of cells underwent expansion, contraction, and memory generation/maintenance phases throughout the lifespan of the animal. Altogether, these findings bring insight to the heterogeneity of the immune T cell response induced by a single immunization with this DNA and strengthen the concept that used of the IFN-γ-ELISPOT assay alone may be insufficient to detect critical T cell responses to candidate HIV vaccines.
Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation
Authors: Al-Alwan Monther M. , Okkenhaug Klaus , Vanhaesebroeck Bart , Hayflick Joel S. , Marshall Aaron J. 
Published: April 2014

Abstract
The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110δ isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110δ signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110δ signaling was specifically inactivated. In contrast, inactivation of p110δ significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110δ-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110δ signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110δ-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110δ signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.
Fas-Associated Death Domain-Containing Protein-Mediated Antiviral Innate Immune Signaling Involves the Regulation of Irf7
Authors: Balachandran Siddharth , Venkataraman Thiagarajan , Fisher Paul B. , Barber Glen N. 
Published: April 2014

Abstract
The induction of type I (αβ) IFN following virus infection is necessary for the stimulation of effective antiviral host defense. In fibroblasts, a subset of primary genes (including those encoding IFN-β and IFN-α4) are induced directly by intracellular dsRNA generated by the virus during its replication. These primary type I IFNs induce expression of IFN regulatory factor (IRF)-7, required for production of a second cascade of IFN-α subtypes and the further establishment of a complete antiviral state. Previously, we had reported on a role for Fas-associated death domain-containing protein (FADD) in the control of TLR-independent innate immune responses to virus infection. Our data in this study demonstrate that FADD is not only required for efficient primary gene induction, but is also essential for induction of Irf7 and effective expression of secondary IFN-αs and other antiviral genes. Ectopic overexpression of IRF-7 partially rescued dsRNA responsiveness and IFN-α production, and a constitutively active variant of IRF-7 displayed normal activity in Fadd−/− murine embryonic fibroblasts. MC159, a FADD-interacting viral protein encoded by the molluscum contagiosum poxvirus was found to inhibit dsRNA-activated signaling events upstream of IRF-7. These data indicate that FADD’s antiviral activity involves regulation of IRF-7-dependent production of IFN-α subtypes and consequent induction of secondary antiviral genes.
Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1
Authors: Ahn Kwang Seok , Sethi Gautam , Aggarwal Bharat B. 
Published: April 2014

Abstract
Numerous recent reports suggest that statins (hydroxy-3-methylglutaryl-CoA reductase inhibitors) exhibit potential to suppress tumorigenesis through a mechanism that is not fully understood. Therefore, in this article, we investigated the effects of simvastatin on TNF-α-induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF-α as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining. This effect of simvastatin correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1 and cyclooxygenase-2), cell survival (Bcl-2, Bcl-xL, cellular FLIP, inhibitor of apoptosis protein 1, inhibitor of apoptosis protein 2, and survivin), invasion (matrix mellatoproteinase-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor); all known to be regulated by the NF-κB. We found that simvastatin inhibited TNF-α-induced NF-κB activation, and l-mevalonate reversed the suppressive effect, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. Simvastatin suppressed not only the inducible but also the constitutive NF-κB activation. Simvastatin inhibited TNF-α-induced IκBα kinase activation, which led to inhibition of IκBα phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-κB-dependent reporter gene expression induced by TNF-α, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF-β-activated kinase 1, receptor-interacting protein, NF-κB-inducing kinase, and IκB kinase β was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of IκB kinase and NF-κB-regulated gene products.
Glucocorticoid Conditioning of Myeloid Progenitors Enhances TLR4 Signaling via Negative Regulation of the Phosphatidylinositol 3-Kinase-Akt Pathway
Authors: Zhang Tian Y. , Daynes Raymond A. 
Published: April 2014

AbstractThe immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Mφs) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-α, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-κB and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during Mφ differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Mφs purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.
Differential Biological Role of CD3 Chains Revealed by Human Immunodeficiencies
Authors: Recio María J. , Moreno-Pelayo Miguel Angel , Kiliç Sara S. , Guardo Alberto C. , Sanal Ozden , Allende Luis M. , Pérez-Flores Verónica , Mencía Angeles , Modamio-Høybjør Silvia , Seoane Elena , Regueiro José R. 
Published: April 2014

AbstractThe biological role in vivo of the homologous CD3γ and δ invariant chains within the human TCR/CD3 complex is a matter of debate, as murine models do not recapitulate human immunodeficiencies. We have characterized, in a Turkish family, two new patients with complete CD3γ deficiency and SCID symptoms and compared them with three CD3γ-deficient individuals belonging to two families from Turkey and Spain. All tested patients shared similar immunological features such as a partial TCR/CD3 expression defect, mild αβ and γδ T lymphocytopenia, poor in vitro proliferative responses to Ags and mitogens at diagnosis, and very low TCR rearrangement excision circles and CD45RA+ αβ T cells. However, intrafamilial and interfamilial clinical variability was observed in patients carrying the same CD3G mutations. Two reached the second or third decade in healthy conditions, whereas the other three showed lethal SCID features with enteropathy early in life. In contrast, all reported human complete CD3δ (or CD3ε) deficiencies are in infants with life-threatening SCID and very severe αβ and γδ T lymphocytopenia. Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3γ deficiencies despite poor thymus output or clinical outcome. We propose a CD3δ ≫ CD3γ hierarchy for the relative impact of their absence on the signaling for T cell production in humans.