bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells
Authors: Cho Seong H. , Yao Zhengbin , Wang Shen-Wu , Alban Rodrigo F. , Barbers Richard G. , French Samuel W. , Oh Chad K. 
Published: April 2014

Abstract
Activin A, a homodimeric protein (βAβA) and a member of the TGF-β superfamily, is involved in the inflammatory repair process. Using cDNA microarray analysis, we discovered strong induction of the activin βA gene in human mast cells (MC) on stimulation with PMA and calcium ionophore (A23187). Activin βA mRNA was also highly induced in primary cultured murine bone marrow MC (BMMC) after stimulation by IgE receptor cross-linking. Secretion of activin A was evident in human mast cell-1 line cells 3 h after stimulation and progressively increased over time. Activin A was present in the cytoplasm of activated but not unstimulated murine bone marrow MC as demonstrated by immunofluorescence studies, suggesting that secretion of activin A by MC was due to de novo synthesis rather than secretion of preformed protein. Activin A also colocalized with human lung MC from patients with asthma by double-immunofluorescence staining. Furthermore, secretion of activin A was significantly increased in the airway of wild-type mice after OVA sensitization followed by intranasal challenge. Secretion of activin A, however, was greatly reduced in MC-deficient WBB6F1-W/Wv mice as compared with wild-type mice, indicating that MC are an important contributor of activin A in the airways of a murine asthma model. Additionally, activin A promoted the proliferation of human airway smooth muscle cells. Taken together, these data suggest that MC-derived activin A may play an important role in the process of airway remodeling by promoting the proliferation of airway smooth muscle.
Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation
Authors: Osawa Yosuke , Nagaki Masahito , Banno Yoshiko , Brenner David A. , Nozawa Yoshinori , Moriwaki Hisataka , Nakashima Shigeru 
Published: April 2014

Abstract
Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.
Distinct Requirements for IL-7 in Development of TCRγδ Cells During Fetal and Adult Life
Authors: Laky Karen , Lewis Julia M. , Tigelaar Robert E. , Puddington Lynn 
Published: April 2014

AbstractTCRγδ-transgenic IL-7−/− mice were generated to determine whether T cells containing productively rearranged TCRγδ genes have additional requirements for IL-7 within the thymus or peripheral lymphoid tissues. Differences in developmental requirements for IL-7 by TCRγδ cells were noted and were linked to derivation from fetal- vs adult-type precursors in the thymus. Although TCRγδ cells are absent from IL-7−/− mice, TCRγδ cells were restored to the thymus and periphery by expression of TCRγδ transgenes. Endogenous TCRγ chains were expressed by IL-7+/− but not IL-7−/− TCRγδ-transgenic mice, providing direct support for findings that IL-7 is necessary for rearrangement and expression of TCRγ genes. The number of TCRγδ thymocytes was 10-fold reduced in TCRγδ-transgenic IL-7−/− embryos; however, adult TCRγδ-transgenic IL-7−/− or IL-7+/− mice had similar numbers of fetal thymus-derived TCRγδ cells in their skin. Thus, fetal TCRγδ cells required IL-7 for TCR rearrangement, but not for proliferation or survival in the periphery. In contrast, the numbers of TCRγδ cells in other tissues of TCRγδ-transgenic IL-7−/− mice were not completely restored. Moreover, coincident with the transition from the first to second wave of T cell precursors maturing in neonatal thymus, thymus cellularity of TCRγδ-transgenic IL-7−/− mice dropped significantly. These data indicated that in addition to TCRVγ gene rearrangement, TCRγδ cells differentiating from late fetal liver or adult bone marrow precursors have additional requirements for IL-7. BrdU incorporation studies indicated that although IL-7 was not required for TCRγδ cell proliferation, it was required to prolong the life span of mature TCRγδ cells.
Regulation of T Cell Activation and Tolerance by Phospholipase Cγ-1-Dependent Integrin Avidity Modulation
Authors: Wells Andrew D. , Liu Qing-Hua , Hondowicz Brian , Zhang Jidong , Turka Laurence A. , Freedman Bruce D. 
Published: April 2014

Abstract
Ag receptor engagement without costimulation induces a tolerant state in CD4+ T cells termed anergy. Anergic CD4+ T cells are primarily characterized by the inability to produce IL-2, but the biochemical basis for this functional defect is not completely understood. We demonstrate that primary CD4+ T cells anergized by costimulatory blockade exhibit impaired TCR-coupled phospholipase C (PLC)γ-1 activation. This defect is associated with the marked reduction of multiple downstream signaling events required for IL-2 transcription, including mobilization of intracellular Ca2+ and activation of the mitogen-activated protein kinase cascade. We also found that primary anergic CD4+ T cells fail entirely to modulate their integrin binding avidity in response to TCR stimulation. Integrin avidity modulation is required for full T cell activation and effector function, and as we show in this study, is completely dependent upon PLCγ-1 activity. Finally, analogs that mimic the actions of diacylglycerol and inositol 1,4,5-triphosphate, the immediate products of PLCγ-1 activity, restored integrin avidity modulation and IL-2 production by anergic T cells. Thus, deficient coupling of PLCγ-1 to the TCR appears to be a central biochemical defect that could potentially account for the failure of multiple functional responses in primary anergic CD4+ T cells.
Communication Between NF-κB and Sp1 Controls Histone Acetylation Within the Proximal Promoter of the Monocyte Chemoattractant Protein 1 Gene
Authors: Boekhoudt Gunther H. , Guo Zhu , Beresford Guy W. , Boss Jeremy M. 
Published: April 2014

Abstract
The induction of the monocyte chemoattractant protein 1 gene (MCP-1) by TNF occurs through an NF-κB-dependent distal regulatory region and an Sp1-dependent proximal regulatory region that are separated by 2.2 kb of sequence. To investigate how these regions coordinate activation of MCP-1 in response to TNF, experiments were performed to examine the role of coactivators, changes in local chromatin structure, and the acetylation of histones at the MCP-1 regulatory regions. An E1a-sensitive coactivator was found to be required for expression. In vivo nuclease sensitivity assays identified changes in response to TNF at both the proximal and distal regions that were dependent on the p65 subunit of NF-κB and Sp1. Chromatin immunoprecipitations used to analyze factor assembly and histone acetylation at the distal and proximal regions showed that Sp1 binding to and histone acetylation of the proximal region was dependent on NF-κB p65. Conversely, Sp1 assembly at the proximal region was required for p65 binding to and acetylation of the distal region, suggesting communication between the two regions during gene activation. These data and the NF-κB p65-dependent histone acetylation of a middle region sequence suggest a potential order for the assembly, acetylation and accessibility of the MCP-1 regulatory regions in response to TNF.
Analysis of the TCR β Variable Gene Repertoire in Chimpanzees: Identification of Functional Homologs to Human Pseudogenes
Authors: Meyer-Olson Dirk , Brady Kristen W. , Blackard Jason T. , Allen Todd M. , Islam Sabina , Shoukry Naglaa H. , Hartman Kelly , Walker Christopher M. , Kalams Spyros A. 
Published: April 2014

AbstractChimpanzees are used for a variety of disease models such as hepatitis C virus (HCV) infection, where Ag-specific T cells are thought to be critical for resolution of infection. The variable segments of the TCR αβ genes are polymorphic and contain putative binding sites for MHC class I and II molecules. In this study, we performed a comprehensive analysis of genes that comprise the TCR β variable gene (TCRBV) repertoire of the common chimpanzee Pan troglodytes. We identified 42 P. troglodytes TCRBV sequences representative of 25 known human TCRBV families. BV5, BV6, and BV7 are multigene TCRBV families in humans and homologs of most family members were found in the chimpanzee TCRBV repertoire. Some of the chimpanzee TCRBV sequences were identical with their human counterparts at the amino acid level. Notably four successfully rearranged TCRBV sequences in the chimpanzees corresponded to human pseudogenes. One of these TCR sequences was used by a cell line directed against a viral CTL epitope in an HCV-infected animal indicating the functionality of this V region in the context of immune defense against pathogens. These data indicate that some TCRBV genes maintained in the chimpanzee have been lost in humans within a brief evolutionary time frame despite remarkable conservation of the chimpanzee and human TCRBV repertoires. Our results predict that the diversity of TCR clonotypes responding to pathogens like HCV will be very similar in both species and will facilitate a molecular dissection of the immune response in chimpanzee models of human diseases.
Threonine Phosphorylation Sites in the β2 and β7 Leukocyte Integrin Polypeptides
Authors: Hilden Tiina J. , Valmu Leena , Kärkkäinen Satu , Gahmberg Carl G. 
Published: April 2014

Abstract
The cytoplasmic domains of integrins play a key role in a variety of integrin-mediated events including adhesion, migration, and signaling. The molecular mechanisms that enhance integrin function are still incompletely understood. Because protein kinases are known to be involved in the signaling and the activation of integrins, the role of phosphorylation has been studied by several groups. The β2 leukocyte integrin subunit has previously been shown to become phosphorylated in leukocytes on cytoplasmic serine and functionally important threonine residues. We have now mapped the phosphorylated threonine residues in activated T cells. After phorbol ester stimulation, all three threonine residues (758–760) of the threonine triplet became phosphorylated but only two at a time. CD3 stimulation leads to a strong threonine phosphorylation of the β2 integrin, but differed from phorbol ester activation in that phosphorylation occurred only on threonine 758. The other leukocyte-specific integrin, β7, has also been shown to need the cytoplasmic domain and leukocyte-specific signal transduction elements for integrin activation. Cell activation with phorbol ester, and interestingly, through the TCR-CD3 complex, caused β7 integrin binding to VCAM-1. Additionally, cell activation led to increased phosphorylation of the β7 subunit, and phosphoamino acid analysis revealed that threonine residues became phosphorylated after cell activation. Sequence analysis by manual radiosequencing by Edman degradation established that threonine phosphorylation occurred in the same threonine triplet as in β2 phosphorylation.
Regulation of MHC Class I Transport in Human Dendritic Cells and the Dendritic-Like Cell Line KG-1
Authors: Ackerman Anne L. , Cresswell Peter 
Published: April 2014

Abstract
Dendritic cells (DCs) progress through distinct maturational phases; immature DCs capture Ag while mature DCs are optimized for Ag presentation. Proper control of immunity requires regulated compartmentalization of MHC class II molecules. We report that DCs also regulate MHC class I trafficking throughout maturation. Although mature human DCs express high levels of surface MHC class I, immature DCs exhibit lower surface levels while retaining MHC class I-peptide complexes in the Golgi. A cell line, KG-1, behaves similarly. We confirm the similarity of KG-1 to DCs by demonstrating its capacity to present exogenous Ags in an MHC class I-restricted fashion to CD8+ T cell hybridomas, a phenomenon called cross-presentation. Biochemical characterization of MHC class I trafficking throughout maturation showed that, in early KG-1 dendritic-like cells, surface arrival of MHC class I-peptide complexes is delayed by their retention in the Golgi. In mature dendritic-like cells, these complexes relocate to the surface and their stability increases, concomitant with up-regulation of costimulatory molecules. Maturation induces qualitative changes in the MHC class I-associated peptide repertoire demonstrated by increased thermostability. The differential processing of MHC class I throughout maturation may prevent premature immune activation while promoting T cell responses in lymph nodes to Ags acquired at sites of inflammation.
The FcRγ Subunit and Syk Kinase Replace the CD3ζ-Chain and ZAP-70 Kinase in the TCR Signaling Complex of Human Effector CD4 T Cells
Authors: Krishnan Sandeep , Warke Vishal G. , Nambiar Madhusoodana P. , Tsokos George C. , Farber Donna L. 
Published: April 2014

Abstract
The TCR-mediated signals required to activate resting T cells have been well characterized; however, it is not known how TCR-coupled signals are transduced in differentiated effector T cells that coordinate ongoing immune responses. Here we demonstrate that human effector CD4 T cells up-regulate the expression of the CD3ζ-related FcRγ signaling subunit that becomes part of an altered TCR/CD3 signaling complex containing CD3ε, but not CD3ζ. The TCR/CD3/FcRγ complex in effector cells recruits and activates the Syk, but not the ZAP-70, tyrosine kinase. This physiologic switch in TCR signaling occurs exclusively in effector, and not naive or memory T cells, suggesting a potential target for manipulation of effector responses in autoimmune, malignant, and infectious diseases.
Genetically Resistant Mice Lacking MyD88-Adapter Protein Display a High Susceptibility to Leishmania major Infection Associated with a Polarized Th2 Response
Authors: Muraille Eric , De Trez Carl , Brait Maryse , De Baetselier Patrick , Leo Oberdan , Carlier Yves 
Published: April 2014

Abstract
Host resistance to the intracellular protozoan Leishmania major is highly dependent on IL-12 production by APCs. Genetically resistant C57BL/6 mice develop IL-12-mediated Th1 immune response dominated by IFN-γ and exhibit only small cutaneous lesions that resolve spontaneously. In contrast, because of several genetic differences, BALB/c mice develop an IL-4-mediated Th2 immune response and a chronic mutilating disease. Myeloid differentiation marker 88 (MyD88) is an adaptator protein that links the IL-1/Toll-like receptor family to IL-1R-associated protein kinase. Toll-like receptors recognize pathogen associated molecular patterns and are crucially implicated in the induction of IL-12 secretion by APC. The role of MyD88 protein in the development of protective immune response against parasites is largely unknown. Following inoculation of L. major, MyD88−/− C57BL/6 mice presented large footpad lesions containing numerous infected cells and frequent mutilations. In response to soluble Leishmania Ag, cells from lesion-draining lymph node showed a typical Th2 profile, similar to infected BALB/c mice. IL-12p40 plasma level collapses in infected MyD88−/− mice compared with infected wild-type C57BL/6 mice. Importantly, administration of exogenous IL-12 rescues L. major-infected MyD88−/− mice, demonstrating that the susceptibility of these mice is a direct consequence of IL-12 deficiency. In conclusion, MyD88-dependent pathways appear essential for the development of the protective IL-12-mediated Th1 response against the Leishmania major parasite. In absence of MyD88 protein, infected mice develop a nonprotective Th2 response.
Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells
Authors: Kawamura Tatsuyoshi , Gatanaga Hiroyuki , Borris Debra L. , Connors Mark , Mitsuya Hiroaki , Blauvelt Andrew 
Published: April 2014

Abstract
APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24+ DC were then enriched by negative selection of CD4+HIV p24− DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4+ T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4+ T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4+ T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4+ T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4+ T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4+ T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.
Persistence of Lesions in Suppressor of Cytokine Signaling-1-Deficient Mice Infected with Leishmania major
Authors: Bullen Denise V. R. , Baldwin Tracey M. , Curtis Joan M. , Alexander Warren S. , Handman Emanuela 
Published: April 2014

Abstract
To investigate the role of the cytokine IFN-γ and its negative regulator, the suppressor of cytokine signaling-1 (SOCS1) in the progression of cutaneous leishmaniasis, we infected mice lacking a single copy of the gene encoding SOCS1 (SOCS1+/−), mice lacking both copies of IFN-γ (IFN-γ−/−), or mice lacking copies of both SOCS1 and IFN-γ (SOCS1−/− IFN-γ−/−), with a moderate dose of 103 or 104 of the most virulent stage of parasites, metacyclic promastigotes. Surprisingly, SOCS1+/− mice developed larger lesions than wild-type mice, although the parasite load in the draining lymph node was not significantly altered. These mice also developed apparently normal Th1 responses, as indicated by elevated levels of IFN-γ and low levels of IL-4 and IL-10. The persistence of lesions and the enlargement of draining lymph nodes despite a normal Th1 response and control of parasitemia indicate that there may be a dissociation of the inflammatory pathology and clearance of parasites in SOCS1+/− mice. We also investigated the role of the related suppressor of cytokine signaling, SOCS2, which has been implicated in the development of Th1 immunity. The progression of disease in SOCS2−/− mice did not differ from that in C57BL/6 control mice, suggesting that it is not involved in the host response to Leishmania major infection and supporting the specific role of SOCS1. These results suggest that SOCS1 plays an important role in the regulation of appropriate inflammatory responses during the resolution of L. major infection.
Transient Neutrophil Infiltration After Allergen Challenge Is Dependent on Specific Antibodies and FcγIII Receptors
Authors: Taube Christian , Dakhama Azzeddine , Rha Yeong-Ho , Takeda Katsuyuki , Joetham Anthony , Park Jung-Won , Balhorn Annette , Takai Toshiyuki , Poch Katie R. , Nick Jerry A. , Gelfand Erwin W. 
Published: April 2014

Abstract
Following allergen challenge of sensitized mice, neutrophils are the first inflammatory cells found in bronchoalveolar lavage (BAL) fluid. To determine the underlying mechanism for their accumulation, mice were sensitized to OVA on days 0 and 14, and received, on day 28, a single intranasal challenge (s.i.n.) with either OVA or ragweed. Eight hours after the s.i.n., BAL fluid was obtained. BALB/c mice sensitized and challenged with OVA showed significantly higher total cell counts and numbers of neutrophils in BAL fluid compared to the OVA-sensitized and ragweed-challenged or nonsensitized mice. Levels of neutrophil chemokines in BAL fluid supernatants were markedly elevated in the sensitized and OVA-challenged mice; FcεRI-deficient mice showed comparable numbers of neutrophils and neutrophil chemokines in BAL fluid after s.i.n. But in sensitized mice lacking the Fc common γ-chain and B cell-deficient mice, the number of neutrophils and levels of neutrophil chemokines in BAL fluid were significantly lower. Further, mice lacking the FcγRIII did not develop this early neutrophil influx. Neutrophil infiltration could be induced in naive mice following intranasal instillation of allergen combined with allergen-specific IgG1. In addition, macrophages from sensitized mice were stimulated with allergen and activated to produce neutrophil chemokines. These results demonstrate that neutrophil influx after allergen challenge requires prior sensitization, is allergen-specific, is mediated through FcγRIII, and is dependent on the presence of Ab.
A Peptide Derived from the Parasite Receptor, Complement C2 Receptor Inhibitor Trispanning, Suppresses Immune Complex-Mediated Inflammation in Mice
Authors: Inal Jameel M. , Schneider Brigitte , Armanini Marta , Schifferli Jürg A. 
Published: April 2014

AbstractComplement C2 receptor inhibitor trispanning (CRIT) is a Schistosoma protein that binds the human complement protein, C2. We recently showed that peptides based on the ligand binding region of CRIT inhibit the classical pathway (CP) of complement activation in human serum, using hemolytic assays and so speculated that on the parasite surface CRIT has the function of evading human complement. We now show that in vitro the C2-binding 11-aa C terminus of the first extracellular domain of CRIT, a 1.3-kDa peptide termed CRIT-H17, inhibits CP activation in a species-specific manner, inhibiting mouse and rat complement but not that from guinea pig. Hitherto, the ability of CRIT to regulate complement in vivo has not been assessed. In this study we show that by inhibiting the CP, CRIT-H17 is able to reduce immune complex-mediated inflammation (dermal reversed passive Arthus reaction) in BALB/c mice. Upon intradermal injection of CRIT-H17, and similarly with recombinant soluble complement receptor type 1, there was a 41% reduction in edema and hemorrhage, a 72% reduction in neutrophil influx, and a reduced C3 deposition. Furthermore, when H17 was administered i.v. at a 1 mg/kg dose, inflammation was reduced by 31%. We propose that CRIT-H17 is a potential therapeutic agent against CP complement-mediated inflammatory tissue destruction.