bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of C1 Inhibitor on Inflammatory and Physiologic Response Patterns in Primates Suffering from Lethal Septic Shock
Authors: Jansen Patty M. , Eisele Bernd , de Jong Irma W. , Chang Alvin , Delvos Ulrich , Taylor Fletcher B. , Hack C. Erik 
Published: January 2023

Abstract
We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiologic and inflammatory response in baboons suffering from lethal Escherichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five controls receiving E. coli alone. Of the treatment group, one animal survived and another lived beyond 48 h, whereas all control animals died within 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not prevent the hemodynamic or hematologic changes observed upon E. coli infusion. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. However, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c, indicating substantial inhibition of activation of the contact system and the classical complement pathway, respectively. Furthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest that activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock through an augmentation of the cytokine response.
Differential Activities of Secreted Lymphotoxin-α3 and Membrane Lymphotoxin-α1β2 in Lymphotoxin-Induced Inflammation: Critical Role of TNF Receptor 1 Signaling
Authors: Sacca Rosalba , Cuff Carolyn A. , Lesslauer Werner , Ruddle Nancy H. 
Published: January 2023

Abstract
Lymphotoxin (LT, LTα, TNFβ) is a member of the immediate TNF family that also includes TNF-α and lymphotoxin-β (LTβ). LT is produced by activated lymphocytes and functions as either a secreted homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein LTβ. Secreted LTα3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the membrane-bound heterotrimer LTα1β2 has been shown to interact with a distinct receptor, LTβR. LTα induces inflammation at the sites of expression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and kidney. To determine the role of the various ligands and their receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or LTβ were crossed to RIPLT-transgenic mice. Our results indicate that LTα-induced inflammation is dependent on the interaction of LTα3 with TNFR1, and there is no obvious role for TNFR2, since in its absence, LTα-induced inflammation is quantitatively and qualitatively similar to that seen in the wild type. However, the absence of LTβ results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the infiltrate. These data show a crucial role for the secreted LTα3 signaling via TNFR1 in LTα-induced inflammation, and a separate and distinct role for the membrane LTα1β2 form in this inflammatory process.
A New Role for B Cells in Systemic Autoimmunity: B Cells Promote Spontaneous T Cell Activation in MRL-lpr/lprMice
Authors: Chan Owen , J. Shlomchik Mark 
Published: January 2023

AbstractA conventional view of the pathogenesis of systemic lupus erythematosus has emerged. The role of B cells is to secrete pathogenic autoantibodies, while the role of T cells is to provide help for autoantibody-producing B cells. A problem with this view is that spontaneous T cell activation as well as T cell infiltration of organs such as kidney and skin are prominent features in systemic lupus erythematosus patients and murine models of lupus. The identification of T cell infiltrates, in particular, suggests that autoantibody-mediated damage may be only part of the story and that T cells could also play a primary role in immune-mediated pathology. To test the role of B cells directly, we previously generated autoimmune-prone MRL-lpr/lpr mice that lack B cells. The complete absence of T cell infiltrates in these mice was surprising, and it prompted us to examine whether a key role of B cells in disease evolution is to prime autoreactive T cells. Here we demonstrate, by comparing B cell-deficient and control mice, that the expansion of activated and memory T cells in the MRL-lpr/lpr mouse is indeed highly dependent on B cells. These results suggest a novel role for B cells in autoimmune disregulation.
Cutting Edge: p21-Activated Kinase (PAK) Is Required for Fas-Induced JNK Activation in Jurkat Cells
Authors: Rudel Thomas , Zenke Frank T. , Chuang Tsung-Hsien , Bokoch Gary M. 
Published: January 2023

Abstract
The process of apoptosis is a critical component of normal immune system development and homeostasis, and in many cells this involves signaling through the c-Jun amino terminal kinase (JNK) pathway. In Jurkat T cells, Fas-induced JNK activity is dependent upon activation of the caspase cascades known to be central components of the apoptotic program. We show in Jurkat cell lines expressing a dominant negative PAK construct that PAK signaling is necessary for JNK activation in response to Fas receptor cross-linking. Inhibition of JNK activation induced by Fas does not impair cell death as assessed by DNA fragmentation. However, expression of the catalytically active C terminus of PAK2, which is generated through caspase action during Fas-mediated apoptosis, induces Jurkat cell apoptosis. We conclude that PAK activity resulting from caspase-mediated cleavage is a necessary component of JNK activation induced by Fas receptor signaling and that PAK2 can contribute to the induction of cell death.
Cutting Edge: TCR Stimulation by Antibody and Bacterial Superantigen Induces Stat3 Activation in Human T Cells
Authors: Gerwien Jens , Nielsen Mette , Labuda Tord , Nissen Mogens H. , Svejgaard Arne , Geisler Carsten , Röpke Carsten , Ødum Niels 
Published: January 2023

Abstract
Recent data show that TCR/CD3 stimulation induces activation of Stat5 in murine T cells. Here, we show that CD3 ligation by mAb and Staphylococcal enterotoxin (SE) induce a rapid, gradually accumulating, long-lasting tyrosine, and serine phosphorylation of Stat3 (but not Stat5) in allogen-specific human CD4+ T cell lines. In contrast, IL-2 induces a rapid and transient tyrosine and serine phosphorylation of Stat3. Compared with IL-2, CD3 ligation induces a delayed Stat3 binding to oligonucleotide probes from the ICAM-1 and IL-2Rα promoter. CD3-mediated activation of Stat3 is almost completely inhibited by a Src kinase inhibitor (PP1), whereas IL-2-induced Stat3 activation is unaffected. In conclusion, we show that CD3 ligation by mAb and SE triggers a rapid, PP1-sensitive tyrosine and serine phosphorylation of Stat3 in human CD4+ T cells. Moreover, we provide evidence that TCR/CD3 and IL-2 induce Stat3 activation via distinct signaling pathways.
Bruton’s Tyrosine Kinase Deficiency in Macrophages Inhibits Nitric Oxide Generation Leading to Enhancement of IL-12 Induction
Authors: Mukhopadhyay Sangita , George Anna , Bal Vineeta , Ravindran Balachandran , Rath Satyajit 
Published: January 2023

Abstract
We show that macrophages of X-linked immunodeficient mice with a mutant nonfunctional Bruton’s tyrosine kinase produce less NO than wild-type macrophages in response to a variety of stimuli. Induction of the inducible NO synthase (iNOS) protein, the transcription factor IFN regulatory factor-1 involved in iNOS expression, and the transcription factor STAT-1 involved in regulating IFN regulatory factor-1 induction are all poorer in X-linked immunodeficient than in wild-type macrophages. On the other hand, induction of IL-12 is higher in X-linked immunodeficient than in wild-type macrophages. Macrophage IL-12 induction is enhanced by iNOS inhibitors such as aminoguanidine and thiocitrulline and is inhibited by NO generation via sodium nitroprusside. There is relative enhancement of IFN-γ production by immune T cells from mice immunized under aminoguanidine cover. Our data thus suggest that Bruton’s tyrosine kinase participates in signaling for iNOS induction via IFN regulatory factor-1 in macrophages and that NO is an inhibitor of IL-12 induction.
Models for Antigen Receptor Gene Rearrangement. II. Multiple Rearrangement in the TCR: Allelic Exclusion or Inclusion?
Authors: Piper Hannah , Litwin Samuel , Mehr Ramit 
Published: January 2023

AbstractThis series of papers addresses the effects of continuous Ag receptor gene rearrangement in lymphocytes on allelic exclusion. The previous paper discussed light chain gene rearrangement and receptor editing in B cells, and showed that these processes are ordered on three different levels. This order, combined with the constraints imposed by a strong negative selection, was shown to lead to effective allelic exclusion. In the present paper, we discuss rearrangement of TCR genes. In the TCR α-chain, allelic inclusion may be the rule rather than the exception. Several previous models, which attempted to explain experimental observations, such as the fractions of cells containing two productive TCRα rearrangements, did not sufficiently account for TCR gene organization, which limits secondary rearrangement, and for the effects of subsequent thymic selection. We present here a detailed, comprehensive computer simulation of TCR gene rearrangement, incorporating the interaction of this process with other aspects of lymphocyte development, including cell division, selection, cell death, and maturation. Our model shows how the observed fraction of T cells containing productive TCRα rearrangements on both alleles can be explained by the parameters of thymic selection imposed over a random rearrangement process.
Strong TCR Ligation Without Costimulation Causes Rapid Onset of Fas-Dependent Apoptosis of Naive Murine CD4+ T Cells
Authors: Kishimoto Hidehiro , Sprent Jonathan 
Published: January 2023

Abstract
Activation-induced cell death of T cells typically occurs late in the primary response after a prior proliferative response. Here, we describe a novel form of cell death in which purified naive murine CD4+ cells undergo apoptosis within 18 h in vitro after strong TCR ligation. Such rapid-onset TCR-mediated death of T cells does not involve cell division and is Fas-dependent, inhibited by CD28 (and IL-6) costimulation and enhanced by IL-4 and IL-7; by contrast, spontaneous death of CD4+ cells cultured alone is Fas-independent and inhibited by IL-4 and IL-7. TCR-mediated Fas-dependent death of CD4+ cells is prevented by combined TCR/Fas ligation and by drugs that inhibit calcineurin-dependent signaling and mitogen-activated protein kinase MEK1 activation.
Priming MHC-I-Restricted Cytotoxic T Lymphocyte Responses to Exogenous Hepatitis B Surface Antigen Is CD4+ T Cell Dependent
Authors: Wild Jens , Grusby Michael J. , Schirmbeck Reinhold , Reimann Jörg 
Published: January 2023

Abstract
MHC-I (Ld)-restricted, S28–39-specific CTL responses are efficiently primed in H-2d BALB/c mice injected with low doses of native hepatitis B surface Ag (HBsAg) lipoprotein particles without adjuvants. Priming of this CTL response by exogenous HBsAg required CD4+ T cell “help” and IL-12: this CTL response could be neither induced in mice depleted of CD4+ T cells by in vivo Ab treatment, nor in (CD4+ T cell-competent or CD4+ T cell-depleted) IL-12-unresponsive STAT4−/− knockout BALB/c mice. Codelivery of oligonucleotides (ODN) with immunostimulating CpG sequences (ISS) with exogenous HBsAg reconstituted the CTL response to exogenous HBsAg in CD4+ T cell-depleted normal mice and in CD4+ T cell-competent and CD4+ T cell-depleted STAT4−/− BALB/c mice. Injection (by different routes) of “naked” pCI/S plasmid DNA encoding HBsAg into IL-12-responsive or –unresponsive BALB/c mice efficiently primed the MHC-I-restricted, HBsAg-specific CTL response. CTL priming was not detectable when CD4+ T cell-depleted animals were subjected to genetic immunization. In vivo priming of the well-characterized CD8+ CTL response to HBsAg in “high responder” BALB/c mice either by exogenous surface lipoprotein particles or by DNA vaccination is thus CD4+ T cell dependent. CTL priming by exogenous HBsAg, but not by genetic immunization, is IL-12 dependent. The dependence of CTL priming by exogenous HBsAg on CD4+ T cells can be overcome by codelivering ODN with ISS motifs, and this “adjuvants effect” operates efficiently in IL-12-unresponsive mice. The data characterize a feature of the adjuvant effect of ISS-containing ODN on CTL priming that may be of major interest for the design of CTL-stimulating vaccines with efficacy in immunodeficiency conditions.
The B Cell Antigen Receptor Activates the Akt (Protein Kinase B)/Glycogen Synthase Kinase-3 Signaling Pathway Via Phosphatidylinositol 3-Kinase
Authors: Gold Michael R. , Scheid Michael P. , Santos Lorna , Dang-Lawson May , Roth Richard A. , Matsuuchi Linda , Duronio Vincent , Krebs Danielle L. 
Published: January 2023

Abstract
We have previously shown that the B cell Ag receptor (BCR) activates phosphatidylinositol (PI) 3-kinase. We now show that a serine/threonine kinase called Akt or protein kinase B is a downstream target of PI 3-kinase in B cells. Akt has been shown to promote cell survival as well as the transcription and translation of proteins involved in cell cycle progression. Using an Ab that specifically recognizes the activated form of Akt that is phosphorylated on serine 473, we show that BCR engagement activates Akt in a PI 3-kinase-dependent manner. These results were confirmed using in vitro kinase assays. Moreover, BCR ligation also induced phosphorylation of Akt of threonine 308, another modification that is required for activation of Akt. In the DT40 chicken B cell line, phosphorylation of Akt on serine 473 was completely dependent on the Lyn tyrosine kinase, while the Syk tyrosine kinase was required for sustained phosphorylation of Akt. Complementary experiments in BCR-expressing AtT20 endocrine cells confirmed that Src kinases are sufficient for BCR-induced Akt phosphorylation, but that Syk is required for sustained phosphorylation of Akt on both serine 473 and threonine 308. In insulin-responsive cells, Akt phosphorylates and inactivates the serine/threonine kinase glycogen synthase kinase-3 (GSK-3). Inactivation of GSK-3 may promote nuclear accumulation of several transcription factors, including NF-ATc. We found that BCR engagement induced GSK-3 phosphorylation and decreased GSK-3 enzyme activity. Thus, BCR ligation initiates a PI 3-kinase/Akt/GSK-3 signaling pathway.
The HSC73 Molecular Chaperone: Involvement in MHC Class II Antigen Presentation
Authors: Panjwani Naveed , Akbari Omid , Garcia Sylvie , Brazil Melanie , Stockinger Brigitta 
Published: January 2023

Abstract
Heat shock proteins (HSP) are conserved proteins, many of which share the ability for indiscriminate peptide binding and ATPase-coupled peptide release. In this paper, we show that heat shock cognate protein (HSC)73, a constitutively expressed member of the HSP70 family, could be a candidate for chaperone activity within the MHC class II presentation pathway. HSC73 expression in macrophages was shown to overlap with expression of MHC class II; overexpression of HSC73 in stable transfectants of a macrophage line markedly enhanced their presentation of exogenous Ag without affecting presentation of processing independent peptide. Ag from an exogenous source was demonstrated to associate with HSC73 in macrophages, and this association was sensitive to ATP treatment and inhibited by deoxyspergualin, an immunosuppressive agent that has previously been shown to bind specifically to HSC73. Furthermore, deoxyspergualin reduced Ag presentation by macrophages in relation to the amount of HSC73 expressed in these cells. The data are consistent with a potential role for HSC73 in binding and protecting peptides from extensive degradation and/or facilitating the kinetics of peptide transfer to MHC class II molecules.
Regulatory Role of Peritoneal NK1.1+αβ T Cells in IL-12 Production DuringSalmonellaInfection
Authors: Naiki Yoshikazu , Nishimura Hitoshi , Kawano Tetsu , Tanaka Yujiro , Itohara Shigeyoshi , Taniguchi Masaru , Yoshikai Yasunobu 
Published: January 2023

AbstractNK1.1+αβ T cells emerge in the peritoneal cavity after an i.p. infection with Salmonella choleraesuis in mice. To elucidate the role of the NK1.1+αβ T cells during murine salmonellosis, mice lacking NK1.1+αβ T cells by disruption of TCRβ (TCRβ−/−), β2m (β2m−/−), or Jα281 (Jα281−/−) gene were i.p. inoculated with S. choleraesuis. The peritoneal exudate T cells in wild type (wt) mice on day 3 after infection produced IL-4 upon TCRαβ stimulation, whereas those in TCRβ−/−, β2m−/−, or Jα281−/− mice showed no IL-4 production upon the stimulation, indicating that NK1.1+αβ T cells are the main source of IL-4 production at the early phase of Salmonella infection. Neutralization of endogenous IL-4 by administration of anti-IL-4 mAb to wt mice reduced the number of Salmonella accompanied by increased IL-12 production by macrophages after Salmonella infection. The IL-12 production by the peritoneal macrophages was significantly augmented in mice lacking NK1.1+αβ T cells after Salmonella infection accompanied by increased serum IFN-γ level. The aberrantly increased IL-12 production in infected TCRβ−/− or Jα281−/− mice was suppressed by adoptive transfer of T cells containing NK1.1+αβ T cells but not by the transfer of T cells depleted of NK1.1+αβ T cells or T cells from Jα281−/− mice. Taken together, it is suggested that NK1.1+αβ T cells eliciting IL-4 have a regulatory function in the IL-12 production by macrophages at the early phase of Salmonella infection.
AND-34, a Novel p130Cas-Binding Thymic Stromal Cell Protein Regulated by Adhesion and Inflammatory Cytokines
Authors: Cai Dongpo , Clayton Linda K. , Smolyar Alex , Lerner Adam 
Published: January 2023

Abstract
We have characterized a novel cDNA whose steady state mRNA levels rise in the thymus 2 to 6 h following the induction of CD4+CD8+ thymocyte apoptosis by in vivo cross-linking of CD3ε. This cDNA, AND-34-1, contains an open reading frame (ORF) encoding a protein with an amino-terminal Src homology 2 (SH2) domain and a carboxyl-terminal domain homologous to GDP-exchange factors (GEFs). Northern analysis demonstrates widespread expression of the AND-34 gene. Anti-CD3ε treatment induces up-regulation of the AND-34 mRNA levels in total thymic RNA but not in RNA from purified thymocytes, suggesting that this transcript is derived from a thymic stromal cell population. IL-1 and TNF increase AND-34 transcript levels in thymic cortical reticular, thymic nurse, and fibroblast cell lines. In the thymic cortical reticular cell line, IL-1 and TNF induce a protein of the predicted 93-kDa size reactive with anti-AND-34 peptide antisera. Fifteen minutes of serum stimulation of vanadate-pretreated AND-34-1-transfected NIH3T3 fibroblasts induces tyrosine phosphorylation of AND-34 as well as coprecipitating 95-, 125-, and 130-kDa proteins. One of these tyrosine phosphorylated proteins is identified as p130Cas (Crk-associated substrate), a signaling molecule previously known to bind to a GDP-exchange factor (C3G) and inducibly associate with the focal adhesion complex. Consistent with such an association, AND-34 tyrosine phosphorylation is induced following adherence of trypsinized fibroblasts to fibronectin or poly-l-lysine-coated surfaces.
Human IL-3 Stimulates Endothelial Cell Motility and Promotes In Vivo New Vessel Formation
Authors: Dentelli Patrizia , Sorbo Lorenzo Del , Rosso Arturo , Molinar Annarita , Garbarino Giovanni , Camussi Giovanni , Pegoraro Luigi , Brizzi Maria Felice 
Published: January 2023

Abstract
Angiogenesis is a critical process for growth of new capillary blood vessels from preexisting capillaries and postcapillary venules, both in physiological and pathological conditions. Endothelial cell proliferation is a major component of angiogenesis and it is regulated by several growth factors. It has been previously shown that the human hemopoietic growth factor IL-3 (hIL-3), predominantly produced by activated T lymphocytes, stimulates both endothelial cell proliferation and functional activation. In the present study, we report that hIL-3 is able to induce directional migration and tube formation of HUVEC. The in vivo neoangiogenetic effect of hIL-3 was also demonstrated in a murine model in which Matrigel was used for the delivery of the cytokine, suggesting a role of hIL-3 in sustaining neoangiogenesis. Challenge of HUVEC with hIL-3 lead to the synthesis of platelet-activating factor (PAF), which was found to act as secondary mediator for hIL-3-mediated endothelial cell motility but not for endothelial cell proliferation. Consistent with the role of STAT5 proteins in regulating IL-3-mediated mitogenic signals, we herein report that, in hIL-3-stimulated HUVEC, the recruitment of STAT5A and STAT5B, by the β common (βc) subunit of the IL-3R, was not affected by PAF receptor blockade.
Cyclic Tensile Stress Exerts Antiinflammatory Actions on Chondrocytes by Inhibiting Inducible Nitric Oxide Synthase
Authors: Gassner Robert , Buckley Michael J. , Georgescu Helga , Studer Rebecca , Stefanovich-Racic Maja , Piesco Nicholas P. , Evans Christopher H. , Agarwal Sudha 
Published: January 2023

Abstract
Continuous passive motion manifests therapeutic effects on inflamed articular joints by an as-yet-unknown mechanism. Here, we show that application of cyclic tensile stress (CTS) in vitro abrogates the catabolic effects of IL-1β on chondrocytes. The effects of CTS are mediated by down-regulation of IL-1β-dependent inducible NO production, and are directly attributed to the inhibition of inducible NO synthase (iNOS) mRNA expression and protein synthesis. The inhibition of iNOS induction by CTS is paralleled by abrogation of IL-1β-induced down-regulation of proteoglycan synthesis. Furthermore, CTS inhibits iNOS expression and up-regulates proteoglycan synthesis at concentrations of IL-1β frequently observed in inflamed arthritic joints, suggesting that the actions of CTS may be clinically relevant in suppressing the sustained effects of pathological levels of IL-1β in vivo. These results are the first to demonstrate that mechanisms of the intracellular actions of CTS in IL-1β-activated chondrocytes are mediated through inhibition of a key molecule in the signal transduction pathway that leads to iNOS expression.