bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collagen-induced arthritis in CD4- or CD8-deficient mice: CD8+ T cells play a role in initiation and regulate recovery phase of collagen-induced arthritis.
Authors: Tada Y , Ho A , Koh D R , Mak T W 
Published: December 2022

Abstract
Collagen-induced arthritis (CIA) is an experimental autoimmune disease induced by immunization with collagen type II (CII). We studied CIA in CD4- or CD8-deficient DBA/1 mice to further define the roles of CD4+ and CD8+ T cells in the disease. CD4-deficient mice developed severe arthritis, and no differences in incidence, clinical course, and severity were observed between CD4 -/- and CD4 +/- mice. Proliferative responses of lymph node T cells to CII was, however, reduced in CD4 -/- mice, and inflamed joints revealed relative accumulation of CD4-CD8-TCR(alpha)(beta)+ cells. A CII-specific T cell line generated from CD4-deficient mice responded to CII in a MHC-restricted fashion and had a CD4-CD8-TCR(alpha)(beta)+ phenotype. Disease incidence in CD8 -/- mice was significantly decreased compared with CD8 +/- mice, even though the severity of arthritis in arthritic mice was not different. These results suggests a role for CD8+ T cells in initiating CIA. Interestingly, CD8-deficient mice were more susceptible to a second induction of arthritis after remission of initial disease, pointing towards an immunoregulatory role for CD8+ T cells. CD8-deficient mice did not, however, show any defect in oral tolerance induction using CII. Taken together, our findings demonstrate that CD4-CD8-TCR(alpha)(beta) cells can trigger systemic arthritis in CD4-deficient mice and that CD8+ T cells can play dual and opposing roles, important both in initiation of CIA and in providing resistance to reinduction of CIA after recovery from initial disease.
Lipopolysaccharide up-regulates platelet-derived growth factor (PDGF) alpha-receptor expression in rat lung myofibroblasts and enhances response to all PDGF isoforms.
Authors: Coin P G , Lindroos P M , Bird G S , Osornio-Vargas A R , Roggli V L , Bonner J C 
Published: December 2022

Abstract
Differential expression of PDGF receptor alpha and beta subunits controls the response of mesenchymal cells to the three PDGF isoforms (AA, AB, and BB). Cultured rat lung myofibroblasts (RLMF) possess abundant PDGF receptor-beta (PDGF-Rbeta) and little PDGF receptor-alpha (PDGF-Ralpha). Here we show that LPS up-regulates expression of PDGF-Ralpha and increases the sensitivity of RLMF to all three PDGF isoforms. Treatment of RLMF for 4 to 48 h with LPS enhanced PDGF-Ralpha surface expression and mRNA 5- to 10-fold but caused no change in expression of PDGF-Rbeta. Both RNA and protein synthesis were necessary for up-regulation of PDGF-Ralpha, and the increase in PDGF-Ralpha mRNA was most likely regulated at the transcriptional level. PDGF-Ralpha up-regulation was not mediated by the IL-1R system and was independent of LPS-binding proteins in serum. Highly confluent cultures of RLMF responded more strongly to LPS than did subconfluent cultures. LPS treatment enhanced the mitogenic and chemotactic responses of RLMF to all PDGF isoforms at least threefold. We postulate that signal transduction by PDGF-receptor alphabeta heterodimers was important in the enhanced responses to PDGF-AB and -BB. We propose that regulation of PDGF-Ralpha is a critical event in the genesis of pulmonary fibroproliferative diseases.
Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide.
Authors: Magazine H I , Liu Y , Bilfinger T V , Fricchione G L , Stefano G B 
Published: December 2022

Abstract
We evaluated the contribution of nitric oxide (NO) to morphine-induced rounding of spontaneously activated (mobile) ameboid human monocytes, granulocytes, or arterial endothelial cells and invertebrate immunocytes and microglia. Morphine induced significant rounding and inactivation of ameboid cells within 20 min except for arterial endothelial cells, which became rounded 24 h after morphine exposure. The effects of morphine on cell conformation were blocked in the presence of N-nitro-L-arginine, a nitric oxide synthase inhibitor. Treatment of cells with the NO donor, sodium nitroprusside, induced cell rounding similar to that observed following morphine exposure, suggesting that NO release may mediate morphine-induced changes in cell conformation. The contribution of NO release to morphine-induced cell rounding was determined by direct evaluation of NO concentration in real-time using a NO-specific amperometric probe. Significant increases in NO concentration were observed 2 min after morphine stimulation, whereas morphine-induced NO release was markedly impaired by pretreatment with N-nitro-L-arginine or the opiate alkaloid antagonist, naloxone. In contrast, opioid peptides failed to induce NO release, consistent with our previous observations that demonstrated the failure of opioid peptides to promote cell rounding. Taken together, these data suggest that morphine-induced NO release may be mediated by activation of the opiate alkaloid-selective, opioid peptide-insensitive micro3 receptor, and that functional coupling of morphine to NO production has been conserved during evolution and may modulate cellular activation.
Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide.
Authors: Nick J A , Avdi N J , Gerwins P , Johnson G L , Worthen G S 
Published: December 2022

Abstract
Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis and the adult respiratory distress syndrome. The intracellular signaling pathway that results in cellular responses following LPS stimulation in neutrophils is unknown. We report that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Partial purification of a p38 MAP kinase by ion exchange chromatography established it as distinct from the p42/p44 (extracellular signal-regulated kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the presence of plasma containing the LPS-binding protein. This intracellular signaling pathway is independent of protein kinase C and does not involve Raf, MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal kinases.
Inhibition by CTLA4Ig of experimental allergic encephalomyelitis.
Authors: Arima T , Rehman A , Hickey W F , Flye M W 
Published: December 2022

Abstract
B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can block this interaction and prevent specific T cell activation. The development of fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in susceptible female Lewis rats was optimized by immunization with 20 mg of guinea pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen uniformly resulted in the development of severe clinical neurologic signs of EAE with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the incidence, delayed the onset, and reduced the severity of clinical EAE (p = 0.0002 vs control by the Mann-Whitney U test) enough to completely prevent fatal EAE, whereas treatment with control human IgG had no effect. Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin basic protein and proteolipid protein) by lymph node cells from animals immunized with guinea pig spinal cord 10 days before was also significantly suppressed in vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could be completely prevented by the daily i.p. administration, from day 0 to 10, of exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell-mediated EAE in the rat.
beta2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice.
Authors: Christianson G J , Blankenburg R L , Duffy T M , Panka D , Roths J B , Marshak-Rothstein A , Roopenian D C 
Published: December 2022

Abstract
MRL-lpr/lpr mice develop a distinctive immunologic disease characterized by accumulation of unusually large numbers of T cells in the peripheral lymphoid organs. Most of the accumulating T cells express an alpha beta-TCR but are peculiar in that they express neither CD4 nor CD8 co-ligands. Concurrent with lymphoaccumulation of such double negative (DN) T cells, MRL-lpr/lpr mice develop a lethal systemic lupus erythematosus-like autoimmune syndrome. This study focuses on the role of MHC class I molecules in this latter pathologic process. Highly backcrossed class I molecule-deficient MRL and MRL-lpr mice carrying a functionally defective allele of the gene beta 2-microglobulin (B2m) were produced. Class I deficient MRL-lpr/lpr mice demonstrated a substantial reduction in DN T cells, confirming other reports indicating that most DN T cells arise from progenitors positively selected on MHC class I molecules. Significantly, class I-deficient MRL-lpr/lpr mice also demonstrated a diminution of every autoimmune disease indicator analyzed including hypergammaglobulinemia; autoantibodies including anti-DNA, anti-Smith antigen, and rheumatoid factor; and glomerulonephritis. The results indicate that class I-dependent T cells are crucial not only for the development of DN T cells, but for multiple features of the MRL-lpr/lpr systemic lupus erythematosus syndrome. Moreover, the pattern of hypergammaglobulinemia suggests that the requirement for MHC class I proteins is restricted temporally to later stages of the disease.
Exploitation of the Vbeta8.2 T cell receptor in protection against experimental autoimmune encephalomyelitis using a live vaccinia virus vector.
Authors: Chunduru S K , Sutherland R M , Stewart G A , Doms R W , Paterson Y 
Published: December 2022

Abstract
This study takes advantage of the predominant usage of Vbeta8.2 by the TCRs of encephalitogenic T cells specific for myelin basic protein. Vaccinia virus recombinants expressing Vbeta8.2 (VVbeta8.2) 8.2) and Vbeta3 (VVbeta 3) proteins were constructed, and their abilities to confer protection against experimental autoimmune encephalomyelitis (EAE) induction in H-2u mice were examined. Mice immunized with VVbeta8.2 developed very mild EAE by comparison with mice that were vaccinated with VVbeta3, which developed severe clinical symptoms. This reduction in EAE correlated with a diminished T cell proliferative response to myelin basic protein in the mice that received VVbeta8.2 compared with that in mice receiving VVbeta3.
Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis.
Authors: Moller D R , Forman J D , Liu M C , Noble P W , Greenlee B M , Vyas P , Holden D A , Forrester J M , Lazarus A , Wysocka M , Trinchieri G , Karp C 
Published: December 2022

Abstract
Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by the expansion of activated oligoclonal CD4+ T cells and macrophages at sites of disease. To investigate the immunopathogenesis of sarcoidosis, we analyzed patterns of cytokine expression in bronchoalveolar lavage cells and fluid from patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis and from normal volunteers. We found dominant type 1 cytokine expression, with elevated mRNA and protein levels of IFN-gamma, but not IL-4, in sarcoid lung cells and fluid compared with those in normal samples. To define immunoregulatory mechanisms important to this type 1 response, we analyzed the expression of IL-12 and IL-10 in lung cells and fluid. Using semiquantitative PCR, we found significantly higher mRNA expression of the regulated IL-12 p40 subunit, but not IL-10, in sarcoid compared with normal lung cells. Consistent with these observations, strikingly elevated levels of p40 protein were found in sarcoid compared with normal bronchoalveolar lavage fluid. Unstimulated and Staphylococcus aureus-stimulated sarcoid alveolar macrophages produced greater amounts of IL-12 than normal alveolar macrophages when cultured in vitro. We hypothesize that sarcoidosis is a Th1-mediated disease driven by chronic, dysregulated production of IL-12 at sites of disease.
Restriction of the TCR repertoire inhibits the development of memory T cells and prevents autoimmunity in lpr mice.
Authors: Perkins D L , Listman J A , Marshak-Rothstein A , Kozlow W , Kelley V R , Finn P W , Rimm I J 
Published: December 2022

Abstract
The lpr mutation, a disruption of the fas gene, induces spontaneous autoimmunity characterized by high titers of autoantibodies, lymphadenopathy, autoreactive T cells, and early mortality. The mechanism of autoimmunity, however, remains unknown. The driving force for disease could result from the T cell recognition of autoantigen or, alternatively, an intrinsic T cell defect that promotes autoreactivity. We investigated the role of antigen-TCR interaction in the pathogenesis of lpr autoimmunity by transferring the DO-11.10 TCR beta-chain transgene (Vbeta8.2-Dbeta1.1-Jbeta1.1) to the MRL-lpr/lpr background producing the MRL-lprbeta strain. Our results show that the MRL-lpr beta transgenic strain has increased survival, lower titers of autoantibodies, and decreased lymphadenopathy compared with nontransgenic littermates. These beneficial effects were associated with decreased expansion of CD4+ T cells expressing memory phenotypes (CD44+, CD45RB-, and LECAM-) in the transgenic compared with nontransgenic strains. A role for impaired recognition of autoantigen by T cells expressing the TCR transgene was suggested by comparing the phenotypes of Vbeta8.2+ (transgene+) vs Vbeta8.2- (transgene-) CD4+ T cells within the transgenic mice. These experiments show that Vbeta8.2- T cells, which express endogenously rearranged TCR, are the major contributors to the expansion of memory T cells in the transgenic mice. In contrast, T cells with memory phenotypes expand similarly in both the Vbeta8.2+ and Vbeta8.2- subsets of nontransgenic mice. Based on these results, we hypothesize that TCR recognition of autoantigen is a major contributor to autoimmunity in lpr mice and that T cells expressing a memory phenotype are perpetrators of this process.
MEK1 and the extracellular signal-regulated kinases are required for the stimulation of IL-2 gene transcription in T cells.
Authors: Whitehurst C E , Geppert T D 
Published: December 2022

Abstract
TCR engagement stimulates the activation of the protein kinase Raf-1. Active Raf-1 phosphorylates and activates the mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase 1 (MEK1), which in turn phosphorylates and activates the MAP kinases/extracellular signal regulated kinases, ERK1 and ERK2. Raf-1 activity promotes IL-2 production in activated T lymphocytes. Therefore, we sought to determine whether MEK1 and ERK activities also stimulate IL-2 gene transcription. Expression of constitutively active Raf-1 or MEK1 in Jurkat T cells enhanced the stimulation of IL-2 promoter-driven transcription stimulated by a calcium ionophore and PMA, and together with a calcium ionophore the expression of each protein was sufficient to stimulate NF-AT activity. Expression of MEK1-interfering mutants inhibited the stimulation of IL-2 promoter-driven transcription and blocked the ability of constitutively active Ras and Raf-1 to costimulate NF-AT activity with a calcium ionophore. Expression of the MAP kinase-specific phosphatase, MKP-1, which blocks ERK activation, inhibited IL-2 promoter and NF-AT-driven transcription stimulated by a calcium ionophore and PMA, and in addition, MKP-1 neutralized the transcriptional enhancement caused by active Raf-1 and MEK1 expression. We conclude that the MAP kinase signal transduction pathway consisting of Raf-1, MEK1, and ERK1 and ERK2 functions in the stimulation IL-2 gene transcription in activated T lymphocytes.
Deletional mapping of fifteen mouse VH gene families reveals a common organization for three Igh haplotypes.
Authors: Mainville C A , Sheehan K M , Klaman L D , Giorgetti C A , Press J L , Brodeur P H 
Published: December 2022

Abstract
In addition to the content of germ-line variable gene segments, the organization of V genes has been implicated in the development of the Ab repertoire. We have searched the expressed VH genes of BALB/c mice for additional VH gene families and utilized deletion mapping to explore the extent of VH gene family interspersion. We have identified and characterized one new VH gene family (VH15) and extended our previous studies of the Igha and Ighb haplotypes to include a third haplotype (Ighj) using a newly developed panel of pre-B cell lines (CXCB cell lines). We conclude that the Igha, Ighb, and Ighj haplotypes have a similar Igh-V locus structure. A refined deletional map for 15 VH gene families and an individual member of the VHSM7 family (H10) has been constructed based on the deletion profiles of 72 rearranged heavy chain loci. These results demonstrate previously unrecognized examples of interspersion among members of the VHS107, VH10, and VHSM7 families.
Molecular cloning and characterization of murine IL-12 genes.
Authors: Yoshimoto T , Kojima K , Funakoshi T , Endo Y , Fujita T , Nariuchi H 
Published: December 2022

Abstract
IL-12 is a heterodimeric cytokine composed of two covalently linked chains, p40 and p35. p40 expression appears to be restricted to monocytes/macrophages and B cells and is highly regulated, while p35 is more ubiquitously and constitutively expressed. To investigate the mechanism involved in the regulation of IL-12 expression, we molecularly cloned and characterized the murine p40 and p35 genes. The p40 gene spans over 14 kb, consists of eight exons and seven introns, and was shown to be localized on chromosome 11A5-B2 by fluorescence in situ hybridization. A single major transcription initiation site was detected by primer extension analysis, and a TATA box was found at approximately 30 bp upstream from the transcription initiation site. The 5' flanking region preceding the transcription initiation site induced the enhanced expression of a promoterless reporter gene after LPS stimulation when transfected into a macrophage-like cell line. In contrast, the p35 gene spans over 8 kb and consists of seven exons and six introns on chromosome 6C, and multiple transcription initiation sites were detected. The 5' flanking region lacks canonical TATA and CAAT boxes at the appropriate position, but, instead, contains GC-rich sequences and constitutively mediated promoter activity when placed upstream of a promoterless reporter gene and transfected into a B cell lymphoma cell line. Thus, the characteristics of promoter regions of p40 and p35 genes are quite different, and this would account for the different regulations of p40 and p35 expression.
Serum amyloid A binds specific extracellular matrix glycoproteins and induces the adhesion of resting CD4+ T cells.
Authors: Preciado-Patt L , Hershkoviz R , Fridkin M , Lider O 
Published: December 2022

Abstract
Serum amyloid A (SAA), a prototypic acute phase protein reactant, exists naturally in the serum of healthy individuals. However, the levels of SAA in serum and its presence in sites of inflammation increase during certain chronic diseases associated with a local elevation of cytokine concentrations. Although the chemical structure of SAA is defined, its putative immunologic role(s) is still obscure. Nevertheless, it has been shown that 1) SAA acts as a chemoattractant and regulator of the migration of monocytes, polymorphonuclear cells, and T lymphocytes through endothelial cell monolayers; and 2) SAA and its proteolytically degraded N-terminal amyloid A fragment contain an extracellular matrix (ECM)-related cell adhesion epitopes. Herein, we examined whether SAA can associate with specific ECM moieties, and whether immobilized SAA-ECM complexes affect T lymphocyte adhesion. Radiolabeled human rSAA ([125I]rSAA) interacted avidly (Kd = 10(-9) M) and transiently with intact ECM, laminin, and vitronectin, but not with fibronectin or collagen type II. The binding of [125I]rSAA to ECM and laminin was inhibited by unlabeled rSAA and by the AA fragment, but not by the C-terminal portion of SAA (amino acid residues 2-82 and 77-104, respectively). Upon interactions with SAA or amyloid A, immobilized ECM, laminin, and vitronectin induced the adhesion of resting human CD4+ T cells in an apparently beta 1-integrin-mediated manner. Thus, the ECM appears to serve as a temporary anchorage site for SAA and amyloid A, and these ECM-complexed molecules seem to be involved in regulating the recruitment and accumulation of immunocytes in extravascular inflammatory compartments.
Vascular endothelial platelet endothelial adhesion molecule-1 (PECAM-1) expression is decreased by TNF-alpha and IFN-gamma. Evidence for cytokine-induced destabilization of messenger ribonucleic acid transcripts in bovine endothelial cells.
Authors: Stewart R J , Kashour T S , Marsden P A 
Published: December 2022

Abstract
Platelet endothelial cell-adhesion molecule-1 (PECAM-1, CD31) is constitutively expressed by vascular endothelium and concentrates at intercellular junctions. Regulation of PECAM-1 expression on endothelial cells may modulate leukocyte trafficking, angiogenesis, and vascular permeability. Given that cytokine activation induces profound alterations in endothelial phenotype, studies sought to determine whether cytokine treatment modulated PECAM-1 mRNA and protein content in macro- and microvascular endothelial cells. Northern blot analysis revealed expression of PECAM-1 mRNA transcripts in endothelial cells derived from bovine aorta, bovine glomeruli, and human umbilical vein under basal conditions. Treatment of endothelial cells with TNF-alpha and/or IFN-gamma led to dramatic decreases in steady-state levels of PECAM-1 mRNA transcripts. In contrast, reciprocal induction of ICAM-1 mRNA was evident. Actinomycin D chase experiments demonstrated that cytokines selectively destabilize PECAM-1 mRNA transcripts in bovine endothelial cells, decreasing the PECAM-1 mRNA transcript t1/2 from basal values of 15 +/- 2 h to 4 +/- 1 h in TNF-alpha- and IFN-gamma-treated cells (p &lt; 0.005), an effect that appeared to be independent of new protein synthesis. Nuclear run-off analysis demonstrated no change in the rates of PECAM-1 gene transcription in response to cytokines treatment. Immunoblots and quantitative indirect immunofluorescence indicated decreased total cellular and cell-surface PECAM-1 protein expression following cytokine treatment. These findings provide evidence for cytokine-induced reciprocal regulation of transcripts of Ig-like adhesion molecules on vascular endothelium.