bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-11 inhibits macrophage interleukin-12 production.
Authors: Leng S X , Elias J A 
Published: December 2022

Abstract
IL-12 is a heterodimeric cytokine produced by phagocytic and other cells with important physiologic and pathologic properties. Regulated IL-12 production is crucial for the generation of protective Th1 responses to infectious agents. In contrast, IL-12 excess contributes to the pathogenesis of a variety of autoimmune and inflammatory disorders. To further understand the processes regulating IL-12 production, we determined whether IL-11 regulated monocyte/macrophage production of this cytokine moiety. IL-11 did not alter the IL-12 (p70) production of unstimulated THP-1 monocytic cells or human blood monocytes. It did, however, inhibit, in a dose-dependent fashion, the IL-12 production of IFN-gamma plus Staphylococcus aureus Cowan strain 1-stimulated THP-1 cells and stimulated blood monocytes. This inhibition of IL-12 protein production was associated with a proportionate decrease in IL-12 p35 and p40 mRNA accumulation. Nuclear run-on assays revealed comparable decreases in IL-12 p35 and p40 gene transcription. IL-11 did not similarly regulate monocyte/macrophage production of IL-8 or macrophage inflammatory protein-1alpha (MIP-1alpha) and IL-6 did not similarly inhibit IL-12 elaboration. These studies demonstrate that IL-11 is a potent inhibitor of monocyte/macrophage IL-12 production and that this inhibitory effect is, at least in part, transcriptionally mediated. They also demonstrate that this inhibition is not the result of a generalized suppression of macrophage effector function and that the ability to inhibit monocyte/macrophage IL-12 production is not a generalized property of all IL-6-type cytokines.
Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection.
Authors: Polyak S , Chen H , Hirsch D , George I , Hershberg R , Sperber K 
Published: December 2022

Abstract
Using the human macrophage hybridoma cell line 43 and primary monocytes, we investigated the regulation of class II expression and intracellular Ag trafficking after HIV-1 infection. The HIV-1-infected human macrophage hybridoma cell line, 43HIV, lost class II Ag expression, as determined by immunofluorescence, immunoprecipitation, and Northern blot analysis, 2 wk after infection. Class II expression could be restored by transfection with the full-length HLA-DR4 cDNA driven by a CMV IE promotor. However, even after transfection, the 43HIV cells were incapable of presenting Ag to MHC-matched Ag-specific T cells. This defect was associated with decreased formation of class II-Ag complexes, and similar findings were observed in primary HIV-1BaL-infected monocytes. We investigated Ag uptake using FITC-labeled tetanus, OVA, and keyhole limpet hemocyanin. There was decreased uptake of all three Ags after HIV-1 infection at different time points after Ag pulsing in the 43HIV cells and in primary HIV-1BaL-infected monocytes. There was colocalization of the FITC-labeled Ags with early (cathepsin D) and late endosomal markers (anti-mannose-6-phosphate receptor), lysosomal markers (CD-63), and acidic compartment markers (3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine) in the uninfected cells, but the level of colocalized Ag was reduced in the 43HIV cells and HIV-1BaL-infected monocytes. Our data suggest that class II expression, formation of class II-Ag complexes, and Ag uptake are impaired in chronically HIV-1-infected monocytic cells, which may contribute to the global immunosuppression observed in AIDS.
CD99 (MIC2) regulates the LFA-1/ICAM-1-mediated adhesion of lymphocytes, and its gene encodes both positive and negative regulators of cellular adhesion.
Authors: Hahn J H , Kim M K , Choi E Y , Kim S H , Sohn H W , Ham D I , Chung D H , Kim T J , Lee W J , Park C K , Ree H J , Park S H 
Published: December 2022

Abstract
Despite the fact that integrin-mediated lymphocyte adhesion is a crucial event for an appropriate immune response, little is known about the mechanisms that control the adhesion and deadhesion processes generated by the engagement of CD99 between various types of immune cells. Here we report that the CD99 gene encodes two distinct proteins with opposite functions in the LFA-1/intercellular adhesion molecule 1 (ICAM-1)-mediated cell adhesion process. The two forms of the CD99 protein are produced by alternative splicing of the CD99 gene transcript. The major form induced homotypic adhesion of the human B lymphoblastoid cell line IM-9, whereas the minor, truncated form inhibited the adhesion process. Activation of the major form of CD99 with anti-CD99 monoclonal antibodies induced rapid aggregation of IM-9 cells, which was blocked by the addition of mAbs to LFA-1 or intracellular adhesion molecule 1. Overexpression of the minor truncated form of CD99 markedly down-regulated the expression of LFA-1. The two forms of CD99 are differentially expressed in most human cells tested and are highly conserved in monkey. Taken together, these observations suggest that the two forms of CD99 function in vivo in both positive and negative regulation of LFA-1-mediated adhesion of lymphocytes during an immune response.
Analysis of polymorphism in porcine MHC class I genes: alterations in signals recognized by human cytotoxic lymphocytes.
Authors: Sullivan J A , Oettinger H F , Sachs D H , Edge A S 
Published: December 2022

Abstract
Elucidation of the mechanism of the immune response against transplanted porcine tissue is critical for the success of xenografting in humans. Both human T cells and NK cells recognize MHC Ags, and human receptors may bind to MHC Ags across species barriers. Molecular characterization of porcine MHC class I clones from two MHC class I loci (P1 and P14) obtained from homozygous inbred miniature swine of three haplotypes (aa, cc, and dd), revealed extensive conservation between loci, suggesting that the genes were products of duplication from a common ancestral sequence. The level of homology between loci was similar to that between the haplotypes at each locus, suggesting that intergenic exchange had limited divergence of these genes. Comparison of the alleles indicated that the polymorphism occurred in the alpha-1 and alpha-2 domains of the class I heavy chain, while the alpha-3 domain was highly conserved among the six genes analyzed. Amino acids in the alpha-2 and alpha-3 domains responsible for the binding of human CD8 to MHC class I were largely conserved in the porcine genes, but several critical residues were altered. Comparison of sequences recognized by human NK cell inhibitory receptors revealed that the residues critical for recognition by these receptors were altered in the porcine genes; thus, the porcine class I molecules would be unable to inhibit lysis by human NK clones characterized to date. This finding provides a likely explanation for the susceptibility of porcine cells to cytolysis by human NK cells.
Heat shock protein 65 induced by gammadelta T cells prevents apoptosis of macrophages and contributes to host defense in mice infected with Toxoplasma gondii.
Authors: Hisaeda H , Sakai T , Ishikawa H , Maekawa Y , Yasutomo K , Good R A , Himeno K 
Published: December 2022

Abstract
We previously reported that gammadelta T cells mediate the expression of endogenous heat shock protein 65 (HSP65) in macrophages of mice with acquired resistance against infection with Toxoplasma gondii. We show here that HSP65 contributes to protective immunity by preventing apoptosis of infected macrophages. Macrophages of BALB/c mice, which readily acquired resistance to T. gondii infection with the low virulence Beverley strain, strongly expressed HSP65, and only a few of these macrophages underwent apoptosis. On the other hand, the BALB/c mice were susceptible to the infection with the high virulence RH strain of T. gondii; their macrophages did not express HSP65 and did undergo apoptosis. Mice depleted of gammadelta T cells using a mAb specific for TCR-gammadelta became highly susceptible to infection even with the Beverley strain. In these mice, HSP65 expression was markedly suppressed, and their infected macrophages died via apoptosis. Apoptosis was induced in cultured macrophages or macrophage cell lines after infection in vitro with the RH strain, whereas apoptosis was prevented when HSP65 was induced in these cells, before infection, by activation with IFN-gamma and TNF-alpha. However, apoptosis associated with infection by T. gondii RH strain was not prevented when HSP65 synthesis was inhibited by introducing an antisense oligonucleotide for this protein into the cells before activation with IFN-gamma plus TNF-alpha. Thus, HSP65 appears to contribute to immunity by preventing the apoptosis of infected macrophages, and the high virulence Toxoplasma appears to have mechanisms that allow these organisms to evade the host defense system by interfering with HSP65 expression.
Enhanced expression of inducible cyclooxygenase with age in murine macrophages.
Authors: Hayek M G , Mura C , Wu D , Beharka A A , Han S N , Paulson K E , Hwang D , Meydani S N 
Published: December 2022

Abstract
Macrophages (Mphi) from old mice produce more PGE2 than those from young mice, contributing to the dysregulation of the immune and inflammatory responses with age. This study was conducted to determine the mechanisms of the age-associated increase in Mphi PGE2 production. PGE2 production is influenced by the availability of the substrate arachidonic acid and by activity of the enzyme cyclooxygenase (Cox). We demonstrate that when the substrate is not the limiting factor, Mphi from old mice have significantly higher LPS-stimulated Cox activity than young mice, indicating that the age-associated increase in PGE2 production is due to increased enzyme activity and not to changes in substrate level. Cox activity is determined by the enzyme level and requires hydroperoxide for activation. Of the two Cox isoforms, Cox 1 is constitutively expressed in nearly all cells; whereas Cox 2 is induced by a wide range of ligands. Analysis of accumulated and de novo synthesis of constitutive Cox 1 and inducible Cox 2 proteins showed no age-related difference in Cox 1 protein levels, but Mphi from old mice had higher accumulated and newly synthesized LPS-stimulated Cox 2 protein levels than young mice. Furthermore, Mphi from old mice had higher LPS-stimulated levels of Cox 2 mRNA compared with those from young mice. Clearly, the age-associated increase in LPS-stimulated PGE2 production is due to increased Cox activity resulting from higher Cox 2 protein and mRNA expression. These findings have significant implications for age-associated immune and inflammatory dysregulation as well as the development of preventive and therapeutic strategies against them.
Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: mannose receptor-mediated phagocytosis initiates IL-12 production.
Authors: Shibata Y , Metzger W J , Myrvik Q N 
Published: December 2022

Abstract
Previous studies showed that mouse spleen cells produced IL-12, TNF-alpha, and IFN-gamma when stimulated with phagocytosable-size chitin particles (N-acetyl-D-glucosamine polymers). To dissect the mechanisms of the cytokine production in this study, spleen cells from BALB/c mice were cultured with 1 to 10 microm chitin particles, heat-killed Corynebacterium parvum vaccine, zymosan, and mannan (a mannose polymer)-coated latex beads (1 microm) at 1, 10, or 100 microg/ml. We found that these particles induced IL-12, TNF-alpha, and IFN-gamma. However, these cytokines were not produced when spleen cells were cultured with soluble chitin, mannan, or laminarin (a polymer of beta-glucan), 1 to 10 microm beta-glucan particles, laminarin-coated latex beads, 1 microm latex beads, 50 to 100 microm chitin particles, or 50 to 100 microm mannan-coated beads. Soluble mannan, but not soluble laminarin, inhibited cytokine production following stimulation with 1 to 10 microm chitin particles, zymosan, or heat-killed C. parvum. In addition, cytochalasin D also inhibited cytokine production. The treatments with soluble mannan or with cytochalasin D, in sharp contrast, did not inhibit LPS-induced IL-12/IFN-gamma production or exogenous IL-12-induced IFN-gamma production. Finally, spleen cells from C3H/HeJ mice also showed comparable levels of IL-12/TNF-alpha/IFN-gamma production when induced by 1 to 10 microm chitin particles. Taken together, our results indicate that mannose receptor-mediated phagocytosis, but not the receptor-mediated pinocytosis, is highly associated with the production of IFN-gamma-inducing extracellular signaling factors such as IL-12 and TNF-alpha. The novel mechanism of phagocytosis-dependent IL-12 production appears to be distinct from that of LPS-induced cytokine production.
Suppression of autoimmune disease and of massive lymphadenopathy in MRL/Mp-lpr/lpr mice lacking tyrosine kinase Fyn (p59fyn).
Authors: Takahashi T , Yagi T , Kakinuma S , Kurokawa A , Okada T , Takatsu K , Aizawa S , Katagiri T 
Published: December 2022

Abstract
MRL/Mp-lpr/lpr (MRL/lpr) mice suffer from a generalized autoimmune disease that includes autoantibody production and glomerulonephritis and develop massive lymphadenopathy characterized by an expanded population of CD4- CD8- B220+ T cells that is derived from autoreactive T cells in the periphery. Some of us previously reported that these atypical T cells overexpressed a gene for tyrosine kinase p59fyn (Fyn). To define the role of Fyn in the renal disease and lymphadenopathy in MRL/lpr mice, we have generated Fyn-deficient MRL/lpr mice whose fyn gene is replaced by the gene for beta-galactosidase. Fyn-deficient MRL/lpr mice developed markedly limited disease and lived more than twice as long as the conventional MRL/lpr mice. In the mutant mice, the production of IgG3 anti-DNA autoantibody was significantly (p &lt; 0.005%) reduced, and glomerular deposits of IgG3 and C3 were remarkably diminished. Ag receptor-mediated proliferative responses of Fyn-deficient splenic T cells were markedly impaired. The mutant mice showed delayed accumulation of the atypical CD4- CD8- B220+ T cells that exhibited a significantly lower activity of ZAP-70 compared with those in the conventional MRL/lpr mice. These data demonstrated that Fyn is involved as a positive regulator in the disease of MRL/lpr mice. Fyn provides a signal for both the expansion of autoreactive T cells and the production of IgG3 anti-DNA autoantibody by B cells. Thus, manipulation of Fyn may improve systemic autoimmune disease in humans.
CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation.
Authors: DeGrendele H C , Kosfiszer M , Estess P , Siegelman M H 
Published: December 2022

Abstract
A defining juncture in the life of a T cell is its encounter with its cognate Ag, resulting finally in effector and/or memory T cells known to express, among other characteristics, increased surface levels of CD44. The requirements for the "activation" of CD44 to bind its major ligand, hyaluronan (HA), and the in vivo role of this interaction remain unresolved. We have recently proposed that the CD44/HA interaction is involved in primary lymphocyte adhesion, leading to extravasation at inflammatory sites. We show here that activation of CD44 and ability to engage in rolling occurs directly through polyclonal as well as Ag-specific TCR-initiated signaling. Using a superantigen, it is primarily the Ag-specific activated Vbeta-bearing cells that are induced to bind HA. In addition, this CD44 activation does not appear to be the result of overt changes in glycosylation. These results connect activation of CD44 on T cells with the initiation of immune responses and suggest potential roles for the CD44/HA interaction.
Regulation of Ku expression in normal murine B cells by stimuli that promote switch recombination.
Authors: Zelazowski P , Max E E , Kehry M R , Snapper C M 
Published: December 2022

Abstract
DNA-dependent protein kinase, the catalytic subunit associated with the Ku heterodimer (Ku70/Ku86), has been implicated in switch recombination. Therefore, we tested whether certain stimuli known to promote switch recombination may act in part by inducing Ku expression. We find that resting B cells contain relatively low levels of nuclear Ku, but that Ku expression can be up-regulated by culturing the cells with two switch stimuli. First, IL-4 and CD40 engagement in combination, but neither of these stimuli acting alone, strongly induce Ku expression; Ku levels rise within 24 h, about 2 days before switch recombination is detected. Second, dextran-conjugated anti-IgD Abs strongly induce Ku expression, which is variably enhanced by IL-5, but not by IL-4. Our data suggest that switch recombination may be regulated, at least in part, through changes in the nuclear expression of Ku.
HEL-Flu: an influenza virus containing the hen egg lysozyme epitope recognized by CD4+ T cells from mice transgenic for an alphabeta TCR.
Authors: Walker W S , Castrucci M R , Sangster M Y , Carson R T , Kawaoka Y 
Published: December 2022

Abstract
Reverse genetics was used to modify the influenza virus genome by inserting the p46-63 sequence of hen egg lysozyme (HEL) into the neuraminidase stalk of the virus. The resulting virus, HEL-Flu, contained the epitopes recognized by CD4+ T cells from 3A9-TCR transgenic mice (C3HTg). Here, we show that HEL-Flu was infectious in the respiratory tract of both C3H and C3HTg mice, the latter animals showing an early, transient morbidity. Splenic dendritic cells and certain cloned populations of splenic macrophages and brain microglia constitutively presented infectious and inactivated HEL-Flu to the T cells in an Ag-specific and MHC class II-restricted manner. These results demonstrate the utility of HEL-Flu in assessing the APC activity for naive T cells; they also extend the previous studies showing that discrete populations of macrophages and microglia constitutively process and present Ag to naive T cells.
Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction.
Authors: Metz D P , Farber D L , Konig R , Bottomly K 
Published: December 2022

Abstract
CD4 T cell activation requires stable contact with APCs. In the present study we demonstrate that anti-CD3-stimulated memory but not naive CD4 T cells fail to form stable conjugates with MHC class II+ APCs and fail to become activated. Early deconjugation by memory CD4 T cells is dependent on CD4-MHC class II interactions in that conjugation is restored when the APC do not express MHC class II or when the class II molecule is mutated at the CD4 binding site. Furthermore, MHC class II-restricted memory-T cells from CD4-deficient mice form stable conjugates, indicating that the CD4 molecule expressed on naive and memory CD4 T cells differs in function and regulates memory but not naive CD4 T cell adhesion to syngeneic APCs in the absence of Ag. This mechanism may have implications for Ag-primed memory CD4 T cells in that primed memory cells, which express an increased number of adhesion molecules, may dissociate from cells in the absence of CD4/TCR co-ligation by the same MHC class II molecule. This would prevent bystander activation and assure efficient recirculation of activated memory T cells in search of Ag-bearing target cells.
Immunocompromised tumor-bearing mice show a selective loss of STAT5a/b expression in T and B lymphocytes.
Authors: Pericle F , Kirken R A , Bronte V , Sconocchia G , DaSilva L , Segal D M 
Published: December 2022

Abstract
Impaired immune responses are frequently observed in tumor-bearing hosts during progression of tumor growth, but the molecular basis of these functional defects remains unclear. To investigate tumor-induced immunosuppression, we first established that lymphocytes from mice bearing s.c. mammary adenocarcinoma (TS/A) tumors were severely impaired in their ability to generate cellular and humoral Ag-specific responses. Lymphocytes from these mice were then screened for abnormalities in the expression of signal transducing proteins known to be involved in the regulation of cellular immunity. Interestingly, purified T and B cells isolated from immunocompromised tumor-bearing mice displayed a marked decrease in the transcription activators STAT5a and -b at the protein level and to a lesser extent at the mRNA level. By contrast, no change in the expression of STAT1, -3, and -6 or of the TCR itself were detected. The correlation in the loss of T and B cell function with the selective decrease in STAT5a/b expression suggests that regulation of the STAT5 signaling pathway may provide a molecular mechanism for modulating the immune system.
Administration of IL-12 induces a CD3+ CD4- CD8- B220+ lymphoid population capable of eliciting cytolysis against Fas-positive tumor cells.
Authors: Tsutsui T , Mu J , Ogawa M , Yu W G , Suda T , Nagaga S , Saji F , Murata Y , Fujiwara H , Hamaoka T 
Published: December 2022

Abstract
The present study investigates the effect of IL-12 administration on the generation of lymphoid cells that exhibit cytotoxicity against tumor cells expressing Fas Ag. Systemic injection of rIL-12 into BALB/c or (B6C3)F1 mice bearing syngeneic CSA1M or OV-HM tumor induced complete tumor regression. CSA1M tumor cells expressed Fas Ag, and exposure of these cells to IFN-gamma enhanced Fas expression. In contrast, Fas Ag was hardly detected on OV-HM cells even after IFN-gamma exposure. Only CSA1M cells were lysed by anti-Fas mAb or cells expressing Fas ligand (FasL), indicating that Fas on CSA1M cells is functional in mediating cell death. An increase in the frequency of lymphoid cells characterized as CD3+ CD4- CD8- B220+ was observed in spleens from both CSA1M and OV-HM tumor-bearing mice after IL-12 treatment. A splenic population enriched in cells with these unique phenotypes exhibited considerable degrees of cytotoxicity against Fas+ CSA1M, but not against Fas- OV-HM tumor cells. The lysis of CSA1M cells was almost completely blocked by addition of Fas-Fc, a fusion protein between the extracellular domain of mouse Fas and the Cgamma1 domain of human Ig. Regressing CSA1M and OV-HM tumor masses after IL-12 treatment exhibited a massive lymphoid cell infiltration and expressed significant levels of FasL mRNA, suggesting the infiltration of FasL-expressing cells to tumor sites. These results indicate that IL-12 induces the expansion of lymphoid cells that exhibit FasL-mediated cytolytic activity and accumulate into regressing tumor masses.
Characterization of anti-single-stranded DNA B cells in a non-autoimmune background.
Authors: Nguyen K A , Mandik L , Bui A , Kavaler J , Norvell A , Monroe J G , Roark J H , Erikson J 
Published: December 2022

Abstract
Anti-DNA Abs are prevalent in the serum of systemic lupus erythematosus (SLE) patients and in the MRL-lpr/lpr mouse model of SLE, but are generally absent in normal individuals. We have studied the regulation of anti-ssDNA B cells in a non-autoimmune (BALB/c) background by using Ig transgenes (Tgs) encoding anti-DNA Abs. In one case, they are present with other non-DNA-binding B cells (the VH3H9 Tg with endogenous light chains); in the other, they are present as an essentially monospecific population (VH3H9/Vkappa8). We have previously observed that serum anti-ssDNA levels in these Tg mice were no higher than those of non-Tg mice, despite the fact that anti-ssDNA B cells dominate the peripheral B cell repertoire. These results suggested that the anti-ssDNA Tg B cells present are functionally inactivated. In this paper, we isolate B cells from VH3H9/Vkappa8 Tg mice to show that this is indeed the case and go on to further define this state. We demonstrate that VH3H9/Vkappa8 Tg B cells have diminished Ig secretion in response to both T-independent and T-dependent stimuli compared with non-Tg controls. VH3H9/Vkappa8 Tg B cells also show suboptimal proliferation in response to anti-IgM F(ab)'2 fragments and LPS, and are phenotypically distinct in expressing decreased total surface Ig. Despite their functional defects, however, VH3H9/Vkappa8 Tg B cells have an in vivo turnover rate comparable to non-Tg B cells, suggesting that they are long lived.