Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of IL-12 on immunoglobulin (Ig) production in vitro in murine chronic graft-vs. -host disease (cGVHD), a lupus-like model of overt B cell activation induced by allogeneic stimulation. Addition of IL-12 to cGVHD splenocytes strongly inhibited total Ig (Igkappa), IgM and IgG1 production. Although IL-12 down-regulated IL-4, IL-5, IL-9 and IL-10 production, its inhibitory activity on Ig production could not be ascribed to down-regulation of these cytokines, as addition of saturating doses of IL-4, IL-5 and/or IL-9 did not reverse the inhibitory activity of IL-12. Interestingly, IL-12 was also found to suppress the stimulating effect of IL-4 and IL-5 on Ig synthesis by cGVHD splenocytes. Several lines of evidence indicated that the inhibitory activity exerted by IL-12 on Ig production was mediated by IFN-gamma. First, IFN-gamma was produced in large amounts upon IL-12 stimulation. Secondly, it displayed a potent inhibitory activity on Ig production. Thirdly, Ig production was also inhibited by IL-18, a recently cloned IFN-gamma-inducing cytokine. Finally, the inhibitory activity of IL-12 was blocked by anti-IFN-gamma monoclonal antibody. We also investigated whether IL-12 down-regulated Ig production by purified cGVHD B cells. We found that IL-12 had only a marginal inhibitory activity on highly purified B cell populations isolated from cGVHD splenocytes and stimulated with IL-4 and IL-5, and that IL-18 was inactive in this respect. However, when the two cytokines were combined, a striking synergy was unmasked not only for IgG1 inhibition but also for IFN-gamma production by these B cell populations. Taken together, our results demonstrate that IL-12 inhibits in vitro Ig production by activated splenocytes through IFN-gamma production and that it synergizes with IL-18 on activated B cells to inhibit Ig production, through up-regulation of IFN-gamma production by B cells.
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PMID:Inhibition of in vitro immunoglobulin production by IL-12 in murine chronic graft-vs.-host disease: synergism with IL-18. 964 83

Cloning of the mouse tag7 gene encoding a novel cytokine is described. The Tag7 protein consists of 182 amino acids. Genomic organization of the tag7 gene and its promoter region remind those of the genes of the tumor necrosis factor locus, although the tag7 gene is not linked to this locus. The gene is located on chromosome 7 at the area that corresponds to band 7A3, which has genetic linkage with lupus-like disease in mouse models. tag7 transcription is essential for lymphoid organs. It is also detected in certain areas of lungs, brain, and intestine and in some tumors. Tag7 protein is detectable in both cell-associated and soluble forms. The soluble form of Tag7 triggers apoptosis in mouse L929 cells in vitro and does not involve NF-kappaB activation. The relationship between Tag7 and tumor necrosis factor family of ligands is discussed.
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PMID:Molecular cloning and characterization of the mouse tag7 gene encoding a novel cytokine. 966 Aug 37

Pristane induces a lupus-like syndrome in nonautoimmune mice characterized by the development of glomerulonephritis and lupus-associated autoantibodies. This is accompanied by overproduction of interleukin (IL)-6, a cytokine linked with autoimmune phenomena. The goal of this study was to evaluate the role of IL-6 in autoantibody production in pristane-induced lupus. BALB/cAn IL-6-deficient (-/-) and -intact (+/+) mice were treated with pristane or phosphate-buffered saline, and autoantibody production was evaluated. Pristane induced high levels of immunoglobulin (Ig)G anti-single-stranded DNA, -double-stranded (ds)DNA, and -chromatin antibodies in IL-6(+/+), but not IL-6(-/-) mice by enzyme-linked immunosorbent assay. High titer IgG anti-dsDNA antibodies also were detected in sera from +/+, but not -/-, mice by Crithidia luciliae kinetoplast staining. The onset of IgG anti-dsDNA antibody production in +/+ mice occurred >5 mo after pristane treatment, well after the onset of nephritis, suggesting that these antibodies are not directly responsible for inducing renal disease. In contrast to anti-DNA, the frequencies of anti-nRNP/Sm and anti-Su antibodies were similar in pristane-treated IL-6(-/-) and IL-6(+/+) mice. However, levels were higher in the +/+ group. These results suggest that IgG anti-DNA and chromatin antibodies in pristane-treated mice are strictly IL-6 dependent, whereas induction of anti-nRNP/Sm and Su autoantibodies is IL-6 independent. The IL-6 dependence of anti-DNA, but not anti-nRNP/Sm, may have implications for understanding the patterns of autoantibody production in lupus. Anti-DNA antibodies are produced transiently, mainly during periods of disease activity, whereas anti-nRNP/Sm antibody levels are relatively insensitive to disease activity. This may reflect the differential IL-6 dependence of the two responses.
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PMID:Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. 973 Sep

During the past year several novel reports have added new knowledge to our understanding of the pathogenesis of system lupus erythematosus (a) a novel pathway for the presentation of autoantigens to autoreactive T cells was revealed. Universally binding nucleosomal epitopes are productively recognized by autoreactive T cells by binding to the T-cell receptor-alpha chain; (b) circulating T cells from patients with lupus commonly display a deficiency of the T-cell receptor zeta chain, and upon ligation of their cell-surface antigen receptor overproduce tyrosine phosphorylated proteins; (c) lupus and lupus nephritis are associated with a low-binding FcgammaRIIIA (CD16) polymorphism that crosses ethnic barriers; (d) the pathogenetic role of the cytokine interleukin-10 is expanding, because it is reportedly overproduced not only by cells from lupus patients but also by cells from their healthy relatives, and its overproduction in vitro is correlated with increased apoptotic cell death and with lymphopenia.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 974 56

Microbial DNA has multiple immune effects including the capacity to induce polyclonal B cell activation and cytokine production in normal mice. We recently described the accelerated induction of anti-DNA Abs in NZB/NZW mice immunized with Escherichia coli (EC) dsDNA; paradoxically these mice developed less renal disease than unimmunized mice or mice immunized with calf thymus DNA. We postulated that alterations in cytokine production induced by bacterial DNA may play a key role in renal protection. To determine the effect of bacterial DNA on cytokine production in NZB/NZW mice, we measured the serum cytokine levels, cell culture supernatant cytokine levels, and number of cytokine-producing splenocytes in NZB/NZW mice injected with EC DNA, calf thymus DNA, or an immune active oligonucleotide. There was a 10- to 25-fold increase in the number of cells secreting IFN-gamma compared with IL-4 in mice immunized with EC DNA. IL-12-secreting cells were also increased by bacterial DNA immunization. In parallel with the increase in IFN-gamma secreting cells, there was a significant rise in serum IFN-gamma levels in mice receiving EC DNA. These results indicate that EC DNA modulates systemic cytokine levels in NZB/NZW mice, selectively increasing IL-12 and IFN-gamma while decreasing IL-4 production. The cytokine response of NZB/NZW mice to bacterial DNA may be of significance in disease pathogenesis and relevant to the treatment of lupus-like disease.
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PMID:Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. 978 Jan 54

Systemic lupus erythematosus (SLE) predominantly affects women (9:1 compared to men) of childbearing age and often decreases its intensity in postmenopausal women, suggesting that sex hormones play a role in its pathogenesis. Comparison of steady-state levels of calcineurin mRNA using RNase protection assays revealed increased calcineurin expression in response to estradiol in cultured T cells from nine female lupus patients. Calcineurin mRNA levels did not increase significantly in T cells from eight age-matched normal control female volunteers. Estrogen-dependent calcineurin mRNA increased in a dose-dependent fashion, while progesterone and dexamethasone did not increase calcineurin mRNA in patient cells. Lupus T cell calcineurin mRNA increased in response to estradiol at 6 h but not at 3 h. Calcineurin phosphatase activity increased in lupus T cell extracts after incubation of cells with estradiol, while phosphatase activity in normal T cells was unaffected by estrogen. Calcineurin expression in T cells from patients with vasculitis and rheumatoid arthritis taking medications similar to those taken by the lupus patients was unaffected by estradiol. This study provides the first evidence for a molecular marker of estrogen action in lupus patients and suggests that estrogen-dependent changes in lupus T cell calcineurin could alter proinflammatory cytokine gene regulation and T-B cell interactions.
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PMID:Gender differences in autoimmune diseases: estrogen increases calcineurin expression in systemic lupus erythematosus. 983 88

It is controversial whether mixed connective tissue disease (MCTD) should be regarded as a distinct disease entity. In the present study, we investigated immunological parameters in patients with MCTD by studying serum levels of immunoglobulins, C-reactive protein (CRP) and cytokines and compared the results to the corresponding values in systemic lupus erythematosus (SLE), in rheumatoid arthritis (RA) patients and in healthy controls. Using the ELISA technique, serum levels of the cytokines interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha) were investigated. Cytokine levels in SLE and MCTD were correlated to disease activity as assessed by systemic lupus activity measure (SLAM). They were also correlated to serum levels of CRP, IgG, IgA and IgM in the three patient groups. The MCTD patients had the highest levels of immunoglobulins, followed by the SLE patients. In contrast, the highest CRP levels were observed in RA patients, followed by the MCTD patients. The MCTD patients had the highest serum levels of IL-10, but also had elevated IFN-gamma and TNF-alpha levels similar to the RA patients. There was no correlation between the investigated cytokine levels and disease activity, as assessed by SLAM. We conclude that MCTD patients have high immunoglobulin levels as well as high CRP levels and that this situation is compatible with the observed increase in both type 1 and type 2 cytokine levels. The findings imply that MCTD shares some distinct immunological properties with both RA and SLE and that MCTD may also be considered as a separate disease entity according to these properties.
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PMID:Increased serum levels of immunoglobulins, C-reactive protein, type 1 and type 2 cytokines in patients with mixed connective tissue disease. 980 36

We have demonstrated that macrophages (Mphi) from young, prediseased, lupus-prone MRL/++ and New Zealand Black/White F1 mice display defective production of TNF-alpha, IL-1, and IL-6, but normal production of IL-10. In an attempt to determine the potential functional implications of this phenotype for autoimmunity, we demonstrate here that endotoxin-activated Mphi from these lupus-prone mice showed dramatically reduced expression of IL-12, a cytokine essential for Th1 responses that may be defective during lupus. IL-12 production was also reduced by Mphi from the control BALB/c strain, compatible with the concept that a genetically programmed deficit in IL-12 levels may underlie the IL-4-dominated BALB/c response to infection by the parasite Leishmania major. Although both IL-12 and TNF-alpha expression defects by Mphi from lupus-prone strains are expressed rapidly after activation, treatment with each cytokine demonstrated that only TNF-alpha contributes to the subsequent dysregulation of Mphi IL-1 and IL-6 expression in these strains, and that the reduced autocrine activity of defective IL-12 or TNF-alpha levels was not causal to each other. Although the intrinsic defect in IL-12 expression by lupus-prone and BALB/c Mphi may lead to defective Th1 responses, these Mphi responded to the Th1-derived cytokine, IFN-gamma, in a normal fashion suggesting a defective role in the induction, rather than the propagation, of Th1 responses in these mice. Our finding of a conserved intrinsic defect in IL-12 production by Mphi from the two principal mouse models of multigenic lupus provides insight into how excessive humoral responses may develop, and perhaps be prevented, in systemic autoimmune disease.
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PMID:Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain. 986 20

MRL-Fas(lpr) mice spontaneously develop a chronic lupus-like renal disease, characterized by immune complex-mediated glomerulonephritis and abundant mononuclear cell infiltration in the interstitium. In the present study we have examined whether the macrophage chemoattractant osteopontin (Opn) could be important in the recruitment of macrophages in this murine model of autoimmune renal injury. We have examined the expression of Opn in the kidney of MRL-Fas(lpr) mice and have correlated Opn synthesis with the degree of macrophage infiltration. Immunofluorescence staining revealed prominent expression of Opn by proximal tubules in MRL-Fas(lpr) mice but not in MRL-++ control mice. Northern blot analysis demonstrated that steady-state transcript levels for Opn mRNA were also significantly increased in MRL-Fas(lpr) kidneys compared with control kidneys. Furthermore, in situ hybridization showed massive Opn mRNA transcripts in proximal tubules in MRL-Fas(lpr) mice but not in controls. The diffuse macrophage infiltration in the kidney of MRL-Fas(lpr) correlated with the enhanced Opn expression. Opn secretion in vitro by cultured renal tubular epithelial cells was upregulated by TNF-alpha and 1,25(OH)2-vitamin D3, whereas no regulation was observed in a control macrophage cell line. We conclude that the enhanced expression of the chemotactic molecule Opn by tubular cells is a prominent feature of murine lupus nephritis and might be promoted by the proinflammatory cytokine environment in MRL-Fas(lpr). The chronic upregulation of Opn could participate in the recruitment of monocytes in the kidney of MRL-Fas(lpr) mice, thereby contributing to the pathogenesis of autoimmune renal disease.
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PMID:Enhanced osteopontin expression and macrophage infiltration in MRL-Fas(lpr) mice with lupus nephritis. 986 26

A significant number of T cells and macrophages infiltrate the kidneys of patients with lupus nephritis. Chemotactic factors, especially monocyte chemoattractant factor-1 (MCP-1) and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), cooperatively facilitate recruitment of mononuclear cells into inflamed tissue. Increased expression of class II MHC molecules and CD40 on renal tubular epithelial cells coupled with upregulation of CD40 ligand (CD40L) and interleukin-2 receptor on infiltrating T cells suggest ongoing cellular immune responses. Recent studies employing knockout mice suggest that the T(H)-1 cytokine interferon-gamma is an important cytokine in amplifying the local immune response of lupus nephritis. Infiltrating mononuclear cells exert their effects on resident renal cells through secretion of soluble factors and/or direct cell to cell contact. These interactions, among others, involve molecules such as CD40/CD40L and adhesion molecules. Studies to better define these molecules are in progress and may provide additional targets for therapeutic intervention. Thus, while autoantibody production and complement activation are the major players in initiating the inflammatory response in lupus nephritis, cellular immune mechanisms mediated through infiltrating mononuclear cells have an important role in its amplification and the progression of renal injury.
Lupus 1998
PMID:Cellular interactions in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney. 988 96


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