bluuebunny/crossref_metadata_2025_split huggingface dataset:
CXCR4 undergoes complex lineage and inducing agent-dependent dissociation of expression and functional responsiveness to SDF-1α during myeloid differentiation
Authors: Gupta Shalley K , Pillarisetti Kodandaram , Aiyar Nambi 
Published: September 2022

AbstractThe CXC chemokine SDF-1 and its receptor CXCR4 mediate myelopoiesis, presumably by regulating the homing of hematopoietic progenitor cells. We used the inducible HL-60 cell line as a model system for comparative analysis of CXCR4 expression during differential maturation into the granulocytic or monocytic phenotypes. Five different measures of CXCR4 expression and functional coupling: mRNA and surface expression, SDF-1-mediated [35S]GTPγS binding, calcium flux, and chemotaxis were examined simultaneously. Granulocytic differentiation with dimethyl sulfoxide induced surface expression of CXCR4 as well as SDF-1-mediated [35S]GTPγS binding and chemotaxis, whereas calcium flux was attenuated by twofold to threefold in HL-60 cells. Conversely, monocytic differentiation with vitamin D3 inhibited surface expression and SDF-1-mediated chemotaxis, even as it induced [35S]GTPγS binding and calcium flux by more than twofold. Sodium butyrate up-regulated all parameters of CXCR4 expression studied. Together, these results demonstrate that CXCR4 expression undergoes complex regulation at multiple checkpoints, with the likely involvement of different G-proteins for signal transduction during cellular differentiation and following activation with SDF-1.
Crotalus durissus terrificussnake venom regulates macrophage metabolism and function
Authors: Sampaio S C , Sousa-e-Silva M C C , Borelli P , Curi R , Cury Y 
Published: September 2022

AbstractIn the present study, we examined the effect of Crotalus durissus terrificus venom on rat macrophage metabolism and function. Two hours after subcutaneous injection of the venom, peritoneal resident (unstimulated), elicited (thioglycollate-stimulated), and activatedMycobacterium bovis strain bacille Calmette Guérin (BCG) macrophages were collected, and their functional and metabolic parameters were analyzed. The venom inhibited spreading and phagocytosis of macrophages. On the other hand, this treatment increased H2O2 and NO production, candidacidal activity, and the activities of key enzymes of glycolysis and glutaminolysis. We also investigated whether the venom could affect macrophage activation by thioglycollate or BCG. The administration of venom 2 h before injection of thioglycollate and BCG or 2 or 3 days after injection of the thioglycollate or BCG, respectively, did not modify the previous observations. These findings suggest that crotalic venom leads the macrophage to an activated state, with high production of oxygen- and nitrogen-reactive species. This cell activation state does not include inflammatory properties of spreading and phagocytosis.
Effects of intracellular zinc depletion on metallothionein and ZIP2 transporter expression and apoptosis
Authors: Cao Jay , Bobo Jeffrey A , Liuzzi Juan P , Cousins Robert J 
Published: September 2022

AbstractZinc is critical for the functional and structural integrity of cells. We have used the monocytic cell line THP-1 as a model in which to study both the responsiveness of metallothionein and ZIP2 transporter expression to zinc depletion induced by the intracellular zinc chelator TPEN [N, N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine] and the extent of concomitant apoptosis. Metallothionein expression increased proportionately with the addition of zinc to the medium and decreased with TPEN treatment. When treated with TPEN, both THP-1 cells and human peripheral blood mononuclear cells exhibited marked decreases in cellular zinc concentrations and increases in ZIP2 mRNA expression. These results suggest that cells attempt to homeostatically adjust to zinc depletion. When THP-1 cells were treated with &gt;5 μM TPEN, cell viability decreased, and cells entered the early stages of apoptosis. These data show that metallothionein and ZIP2 expression are inversely related during zinc depletion and that apoptosis is concurrent with these changes.
IL-10 receptor dysfunction in macrophages during chronic inflammation
Authors: Avdiushko Rita , Hongo David , Lake-Bullock Helene , Kaplan Alan , Cohen Donald 
Published: September 2022

AbstractThe immunosuppressive activity of interleukin-10 (IL-10) makes this cytokine a potentially important clinical tool to reduce inflammatory responses in various diseases. Its efficacy as a therapeutic modality is dependent on the responsiveness of immune cells. We report that macrophages from mice chronically infected with the LP-BM5 retrovirus had a reduced capacity to respond to IL-10 in vitro. The ability of IL-10 to inhibit lipopolysaccharide-induced production of tumor necrosis factor (TNF) α and IL-6 was significantly reduced in both alveolar and peritoneal macrophages from infected versus uninfected mice. IL-10 hyporesponsiveness was not related to direct infection by the retrovirus, because bone marrow-derived macrophages infected in vitro with LP-BM5 were as responsive to IL-10 as were uninfected bone marrow-derived macrophages. TNF-α appeared to contribute to development of IL-10 hyporesponsiveness, because exposure of normal macrophages to TNF-α but not interferon-γ reduced macrophage responsiveness to IL-10. Reverse transcriptase-PCR and flow cytometry demonstrated normal expression of the α and β chains of the IL-10 receptor in macrophages from infected mice, suggesting that IL-10 hyporesponsiveness is not related to a change in receptor expression. The potential role of reduced IL-10 responsiveness in the chronicity of inflammation in this and other diseases is discussed.
Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages
Authors: Misra Uma K , Adlakha Charu L , Gawdi Govind , McMillian Michael K , Pizzo Salvatore V , Laskowitz Daniel T 
Published: September 2022

AbstractApolipoprotein E (ApoE) is a 34-kDa cholesterol transport protein that also possesses immunomodulatory properties. In this study, we demonstrate that ApoE initiates a signaling cascade in murine peritoneal macrophages that leads to increased production of inositol triphosphate with mobilization of intracellular Ca2+ stores. This cascade is inhibited by pretreatment with receptor-associated protein and Ni2+, and it is mediated by a pertussis toxin-sensitive G protein. These properties are characteristic of signal transduction induced via ligand binding to the cellular receptor, lipoprotein receptor-related protein. A peptide derived from the receptor-binding region of ApoE also initiates signal transduction in a manner similar to that of the intact protein, suggesting that this isolated region is sufficient for signal transduction. The ApoE-mimetic peptide competed for binding with the intact protein, confirming that they both interact with the same site. ApoE-dependent signal transduction might play a role in mediating the functional properties of this lipoprotein.
Increased nitric oxide production by airway cells of sensitized and challenged IL-10 knockout mice
Authors: Ameredes Bill T , Zamora Ruben , Gibson Kevin F , Billiar Timothy R , Dixon-McCarthy Barbara , Watkins Simon , Calhoun William J 
Published: September 2022

AbstractThe anti-inflammatory cytokine interleukin (IL)-10 suppresses induciblenitric oxide synthase (iNOS); therefore, NO production should increasein the absence of IL-10. Production of NO (as nitrite) bybronchoalveolar lavage cells of IL-10 knockout (−/−) micewas assessed after ovalbumin sensitization and airway challenge (S/C)and was compared with the IL-10-sufficient, wild-type (WT) C57Bl6.Eosinophil recruitment occurred in S/C WT and IL-10−/−mice, suggesting allergic airway inflammation. Alveolar macrophages(per g mouse) were unchanged (∼3×104 cells) with theexception of a doubling in the S/C IL-10−/− mice(∼6×104 cells, P&lt;0.05). NO production (permillion cells) was doubled in cells from S/C IL-10−/−(15.3 μM) mice compared with WT (7.6 μM, P&lt;0.05). Inhibition of iNOS byl-N5-(1-iminoethyl)-ornithine reduced NOproduction in all S/C mice, confirming that the increase was a resultof up-regulation of iNOS. We conclude that IL-10 is a critical cytokineregulating iNOS in murine airway cells and that its absence can lead toup-regulation of iNOS and development of allergic airwayinflammation.
Profound effect of the absence of IL-4 on T cell responses during infection withSchistosoma mansoni
Authors: Pedras-Vasconcelos João A , Brunet Laura Rosa , Pearce Edward J 
Published: September 2022

AbstractT cell responses of interleukin (IL)-4−/− and wild-type (WT) mice infected with the helper T cell 2 (Th2) response-inducing pathogen Schistosoma mansoni were compared. As expected, given the important role of IL-4 in Th2 response induction, the absence of IL-4 resulted in diminished Th2 responses, apparent as reduced production of IL-4, -5, and -10 by CD4+ cells isolated from the spleens of infected IL-4−/− mice. Surprisingly, these cells produced significantly less interferon (IFN)-γ and proliferated less than did those from infected WT mice after T cell receptor ligation. CD8+ cells isolated from infected IL-4−/− mice also produced less IFN-γ than WT CD8 cells, although there was no difference in the proliferative responses of these cell populations. After infection, spleens of infected IL-4−/− mice did not enlarge to the same extent as those of WT mice, and attrition of the CD8+ cell population within this lymphoid organ was noted. Taken together, the data indicate that in addition to inhibiting Th2 response development, the lack of IL-4 during schistosomiasis significantly affects additional aspects of T cell responses.
Activation-induced cell death of human T-cell subsets is mediated by Fas and granzyme B but is independent of TNF-α
Authors: Gorak-Stolinska Patricia , Truman Jean-Philip , Kemeny David M , Noble Alistair 
Published: September 2022

AbstractHuman primary effector T cells were analyzed for their susceptibility to anti-CD3-induced activation-induced cell death (AICD). Th1 and Tc1 cells were more susceptible to AICD than their type 2 counterparts. Type 1 and type 2 subsets were also found to be differentially susceptible to CD95-mediated apoptosis, although cell-surface expression of CD95 and CD95L was at similar levels on all subsets. A role for CD95 in AICD was confirmed by the addition of anti-CD95L antibodies that partially abrogated AICD. Residual apoptosis could not be accounted for by TNF-α/TNFR interactions because although type 1 cells secreted more TNF-α than type 2 cells, the addition of TNFR:Fc fusion protein did not inhibit AICD. Instead, a reduction in AICD was observed in the presence of EGTA or concanamycin A. The inhibition of apoptosis by a granzyme B inhibitor z-AAD-CMK in Tc1 cells further indicated an involvement of the granule exocytosis mechanism in AICD.
Effect of cross-tolerance between endotoxin and TNF-α or IL-1β on cellular signaling and mediator production
Authors: Ferlito Marcella , Romanenko Olga G , Ashton Sarah , Squadrito Francesco , Halushka Perry V , Cook James A 
Published: September 2022

AbstractAbstract: Endotoxin [lipopolysaccharide (LPS)] tolerance suppresses macrophage/monocyte proinflammatory-mediator production. This phenomenon also confers cross-tolerance to other stimuli including tumor necrosis factor (TNF) α and interleukin (IL)-1β. Post-receptor convergence of signal transduction pathways might occur after LPS, IL-1β, and TNF-α stimulation. Therefore, it was hypothesized that down-regulation of common signaling molecules induces cross-tolerance among these stimuli. LPS tolerance and cross-tolerance were examined in THP-1 cells. Phosphorylation of MAP kinases and degradation of inhibitor κBα (IκBα) DNA binding of nuclear factor-κB (NF-κB), and mediator production were examined. In naive cells, LPS, TNF-α, and IL-1β induced IκBα degradation, kinase phosphorylation, and NF-κB DNA binding. LPS stimulation induced production of TNF-α or TxB2 and degradation of IRAK. However, neither TNF-α nor IL-1β induced IRAK degradation or stimulated TNF-α or TxB2 production in naive cells. Pretreatment with each stimulus induced homologous tolerance to restimulation with the same agonist. LPS tolerance also suppressed LPS-induced TxB2 and TNF-α production. LPS pretreatment induced cross-tolerance to TNF-α or IL-1β stimulation. Pretreatment with TNF-α induced cross-tolerance to LPS-induced signaling events and TxB2 production. Although pretreatment with IL-1β did not induce cross-tolerance to LPS-induced signaling events, it strongly inhibited LPS TNF-α and TxB2 production. These data demonstrate that IL-1β induces cross-tolerance to LPS-induced mediator production without suppressing LPS-induced signaling to MAP kinases or NF-κB activation.
Regulation of nuclear factor κB activation by G-protein-coupled receptors
Authors: Ye Richard D 
Published: September 2022

AbstractAccumulating evidence indicates that G-protein-coupled receptors (GPCRs) play an active role in transcriptional regulation. In leukocytes, activation of receptors for several chemokines and classic chemoattractants has been associated with enhanced expression of proinflammatory cytokines and chemokines. GPCRs in endothelial and epithelial cells also regulate transcription and contribute to the expression of cytokines, adhesion molecules, and growth factors that are essential for extravasation of leukocytes and tissue repair. Nuclear factor (NF) κB is one of the most important transcription factors responsible for the expression of these proinflammatory genes. Recent studies have shown that GPCRs utilize several different pathways to activate NF-κB. These pathways differ from the ones induced by classic cytokines in that they are initiated by heterotrimeric G-proteins, but they converge to IκB phosphorylation and nuclear translocation/modification of the NF-κB proteins. GPCR-induced NF-κB activation provides an effective means for local expression of cytokine and growth factor genes due to the wide distribution of these receptors. Chemokine-induced, GPCR-mediated production of chemokines constitutes an autocrine regulatory mechanism for the growth of certain malignant tumors and enhances the recruitment of leukocytes to sites of inflammation.
Estrogen restores cellular immunity in injured male mice via suppression of interleukin-6 production
Authors: Messingham Kelly A N , Heinrich Scott A , Kovacs Elizabeth J 
Published: September 2022

AbstractThis study examined whether estrogen treatment can improve immunity in male mice after combined ethanol and burn injuries. 17β-Estradiol [estrogen, given subcutaneously (s.c.)] or oil (control) was administered at 30 min and 24 h postinjury. At 48 h postinjury, ethanol/burn-injured mice demonstrated significant suppression of cellular immunity. Estrogen treatment restored the delayed-type hypersensitivity (P&lt;0.01) and splenocyte-proliferative (P&lt;0.05) responses, reduced macrophage interleukin-6 (IL-6) (P&lt;0.05), and increased survival after bacterial challenge (P&lt;0.01). In vitro neutralization of IL-6, combined with macrophage supernatant experiments, confirmed that the beneficial effects of estrogen treatment were mediated through modulation of macrophage IL-6 production. Moreover, estrogen treatment resulted in a decrease in splenic nuclear factor-κB (NF-κB) activation in injured mice. There were no changes in cellular NF-κB or IκBα protein expression or IκBα phosphorylation at serine 32. Taken together, these studies suggest that estrogen treatment of injured male mice improves cellular immunity through direct modulation of NF-κB activation.
cAMP-elevating agents suppress dendritic cell function
Authors: Kambayashi Taku , Wallin Robert P A , Ljunggren Hans-Gustaf 
Published: September 2022

AbstractThe administration of cAMP-elevating agents affects a number of autoimmune and inflammatory conditions. Because dendritic cells (DCs) play a pivotal role in autoimmunity and inflammation, the isolated effects of cAMP-elevating agents on the function of DCs was examined. In a dose-dependent manner, 8-Bromo cAMP, prostaglandin E2, and 3-isobutyl-1-methylxanthine inhibited tumor necrosis factor α release and suppressed antigen presentation by DCs. The same effect was observed with rolipram, a specific inhibitor of phosphodiesterase type 4, but not with inhibitors of other phosphodiesterases. The decreased antigen presentation by DCs was associated with an enhanced production of interleukin (IL)-10 and with lower major histocompatibility complex type II (MHC II) expression. Furthermore, the inhibition of antigen presentation and MHC II expression was significantly reversed by treatment of DCs with neutralizing antibody against IL-10, suggesting the involvement of an IL-10-dependent mechanism. Taken together, these results might explain why certain cAMP-elevating agents such as rolipram are effective in blocking autoimmunity and inflammation.
T-cell-conditioned medium efficiently induces the maturation and function of human dendritic cells
Authors: Kato Kazunori , Takaue Yoichi , Wakasugi Hiro 
Published: September 2022

AbstractWe present evidence that T-cell-conditioned media (TCCM) can efficiently induce human immature dendritic cells (DC) to express high levels of immune accessory molecules commonly found on mature DC. TCCM prepared from cell-free supernatants of anti-CD3-activated T cells contained several soluble factors including CD40-ligand (sCD40L), TNF-α, and IFN-γ. In contrast to moderate up-regulation of costimulatory molecules by the addition of individual cytokines or monocyte-conditioned medium, treatment of immature DC with TCCM induced a marked increase in the expression of costimulatory molecules in a dose-dependent manner. The ability of TCCM to induce such phenotypic changes could be abrogated by neutralizing antibodies specific for CD40L, TNF-α, and IFN-γ, indicating that these factors present in TCCM are mainly implicated in the maturation of DC. Importantly, TCCM-treated DC can produce significantly higher levels of IL-12 and are highly effective stimulators in allogenenic and autologous mixed-lymphocyte reactions. Overall, these findings show that cultivation with TCCM is an efficient approach for the induction of mature DC that should be useful in eliciting antigen-specific immune responses against cancer and viruses.
Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells
Authors: Liu Ru , Aupperle Karl , Terkeltaub Robert 
Published: September 2022

AbstractNeutrophil-dependent inflammation dependent on monosodium urate (MSU)crystal-induced IL-8 expression occurs in gout. MSU crystals activatephagocyte Src family tyrosine kinases and the serine/threonine kinasep70s6k. Thus, using monocytic THP-1 cells, we assessed the potentialfor Src family kinases and p70s6k to mediate MSU-induced IL-8expression. MSU crystals induced phosphorylation of p70s6k and the Srckinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated moreby the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin.PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IκBαand suppressed IκB kinase (IKK) activation and NF-κB binding to theIL-8 promoter, signals that mediate MSU-induced IL-8 expression.Transfection of the native Src inhibitor, C-terminal Src kinase (Csk),also suppressed crystal-induced c-Src, ERK1/2, and IκBαphosphorylation and IL-8 expression. We conclude that Src familytyrosine kinase signaling plays a significant role in MSUcrystal-induced IL-8 expression via stimulation of ERK1/2 pathway andNF-κB activation.
Shiga toxin 1-induced activation of c-Jun NH2-terminal kinase and p38 in the human monocytic cell line THP-1: possible involvement in the production of TNF-α
Authors: Foster Gregory H , Tesh Vernon L 
Published: September 2022

AbstractShiga toxin-producing enterohemorrhagic E. coli infections cause bloody diarrhea, which may progress to life-threatening complications such as the hemolytic-uremic syndrome (HUS). HUS patients frequently have elevated levels of the proinflammatory cytokine tumor necrosis factor α (TNF-α) detectable in urine. Thus, sequelae may develop following the localized production of proinflammatory cytokines within the kidneys. A possible source of these cytokines are macrophages, which respond to the toxins by producing TNF-α. We have shown previously that THP-1 cells produce soluble TNF-α in response to the toxins, whose production requires host-cell tyrosine-kinase activity and toxin-enzymatic activity. To further examine signaling pathways involved in TNF-α expression, we determined that JNK1 and -2 and p38, but not ERK1 or -2, were phosphorylated following toxin exposure. Blockade of p38 activation reduced TNF-α production following Shiga toxin 1 treatment. Finally, we present a model of the ribotoxic stress response triggered in human macrophages by Shiga toxins.
Src kinases regulate PKB activation and modulate cytokine and chemoattractant-controlled neutrophil functioning
Authors: Nijhuis Evert , Lammers Jan-Willem J , Koenderman Leo , Coffer Paul J 
Published: September 2022

AbstractTyrosine phosphorylation is thought to be critical in the regulation of neutrophil functioning, and members of the Src family of tyrosine kinases have recently been shown to be regulated in activated granulocytes. We have used a specific pharmacological inhibitor of Src kinases, pyrazolpyrimidine 1 (PP1), to evaluate the role of Src kinases in cytokine/chemoattractant-induced regulation of neutrophil function. PP1 inhibits PKB phosphorylation but not STAT5 phosphorylation or the activation of MAP kinases by fMLP or GM-CSF. Pretreatment of neutrophils with PP1 and with the PI3K inhibitor LY294002 resulted in a strong inhibition of fMLP-induced superoxide production and cytokine-mediated survival but not fMLP-induced migration. It is interesting that the kinetics of inhibition of actin polymerization and the respiratory burst are very similar. Although initiation of both processes was not affected, sustained activation was inhibited by PP1. Taken together, our results demonstrate a critical role for Src kinases in regulating neutrophil cytotoxic-effector functioning through PI3K-PKB.
Activation of extracellular signal-related kinase by TNF-α controls the maturation and function of murine dendritic cells
Authors: Yanagawa Yoshiki , Iijima Norifumi , Iwabuchi Kazuya , Onoé Kazunori 
Published: September 2022

AbstractFunctional roles of extracellular signal-related kinase (ERK)activation in dendritic-cell (DC) maturation have been unclear. In thepresent study, we investigated the ERK pathway in tumor necrosis factor(TNF)-α-induced maturation of murine spleen-derived DC. TNF-αincreased surface expressions of major histocompatibility(MHC) and costimulatory molecules on DC in a dose-dependentmanner. High (40 ng/ml) and low (0.4 ng/ml) concentrations of TNF-αmarkedly enhanced ERK1/2 activation in DC, and this activation wasblocked completely by PD98059, a selective inhibitor of the ERKpathway. When DC were treated with TNF-α at a low but not a highconcentration, PD98059 notably enhanced surface expressions of the MHCand costimulatory molecules and allostimulatory capability of the DC. Interleukin (IL)-12 production was enhanced significantly by PD98059 in DC treated with low or high concentration of TNF-α. These findingssuggest that TNF-α-induced ERK activation negatively controlsmaturation and IL-12 production in murine DC.