Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We followed cytokine production from induction through disease progression in a murine model of experimental systemic lupus erythematosus (SLE). SLE was induced by immunization with the human monoclonal anti-DNA Ab that bears the common Id designated 16/6 Id. BALB/c and C3H.SW mice that are susceptible to SLE induction and C57BL/6 mice that are resistant were immunized with the 16/6 Id. Cytokine production was tested periodically for 7 mo. Increased production of IL-2 and IFN-gamma, the Th1-type cytokines, was detected in BALB/c and C3H.SW mice 2 to 4 mo following immunization. IL-4 and IL-10, the Th2-type cytokines predominated later in disease course, and peaked 5 mo following disease induction. At this stage the Th1 type cytokines dropped to levels below those observed in controls. IL-4 production also dropped rapidly to very low levels, while IL-10 production decreased but remained above control levels. The ratio of IgG2a/IgG1 of DNA and 16/6 Id-specific Abs peaked at 2 mo following disease induction and decreased later, in concordance with the higher production of Th2-type cytokines. Thus, the development of experimental SLE in mice involves two stages: increased production of Th1-type, followed by increased induction of Th2-type cytokines. High levels of the proinflammatory cytokines, TNF-alpha and IL-1, were maintained throughout disease course. No significant changes were detected in the cytokine profile of C57BL/6 immunocytes following immunization with the 16/6 Id, supporting the possible role of the cytokine network in SLE.
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PMID:Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. 905 40

The objective of the this study was to determine the cytokine profile of aging mice and to establish whether changes in cytokine production account for the fact that aging mice develop a milder disease than the young in response to induced experimental systemic lupus erythematosus (SLE). Cytokine secretion was evaluated in groups of BALB/c and C3H.SW mice at different ages between 2 and 24 months. The production of IL-2, IL-4, IL-10, IFN gamma and TNF alpha was determined in supernatants of ConA-stimulated splenocytes and that of IL-1 in the supernatants of LPS-stimulated peritoneal macrophages. A gradual age-related decline was observed in the production of IL-2 and IFN gamma, whereas the levels of IL-4, IL-10, IL-1 and TNF alpha progressively increased with aging, in unimmunized BALB/c and C3H.SW mice. Experimental SLE was induced in 2 and 10 month old C3H.SW mice by immunization with the monoclonal anti-DNA antibody bearing the 16/6 Id. The characteristic cytokine profile following immunization of 2 month old mice was early increased production of TNF alpha and IL-1, followed by a peak of Th1 type cytokines (IL-2, IFN gamma). At a later stage of the disease, a peak of Th2 type cytokines (IL-4, IL-10) was observed that was concomitant with low levels of Th1 cytokines. In contrast, in the 10 month old mice that were immunized with 16/6 Id only a mild increase in all the above cytokines was observed. We suggest that the lower autoantibody production and moderate clinical manifestations in aging mice with experimental SLE are causally related to the decreased production of pro-inflammatory cytokines at the initial stages of the disease followed by a lower production of both Th1 and Th2 type cytokines.
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PMID:Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus afflicted mice. 922 10

We have previously shown in inbred strains of mice which naturally develop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerulonephritis, suggesting that local tissue complement gene expression could contribute to the pathogenesis of immune complex injury. In this study, we investigated the synthesis of complement proteins in glomerular epithelial cells (GECs) and its regulation. Using biosynthetic labelling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases in the synthesis of all these proteins. Both factor B and C3 proteins were increased following addition of either IL-1beta, IL-6 or TNF-alpha to GEC cultures; however, these cytokines did not increase either C2, C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected the biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse-transcriptase polymerase chain reaction showed that these cytokine effects were pretranslational as there was enhancement of factor B mRNA expression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis, where it is likely that local complement production in GECs is independently regulated by cytokines, derived from resident glomerular mesangial cells or infiltrating monocyte/macrophages and T cells.
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PMID:Differential cytokine regulation of complement proteins in human glomerular epithelial cells. 922 27

These data establish that cytokines, such as IL-1, can act on specific receptors within the brain to induce many symptoms of sickness. A number of inflammatory stimuli in the periphery can activate both the transcription and translation of IL-1 within the central nervous system. It will now be important to determine if similar central IL-1 pathways are activated during SLE and whether these central inflammatory cytokines are involved in the neurologic complications that often accompany this disease.
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PMID:Central interleukin-1 receptors as mediators of sickness. 929 49

We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and NZB/W F1 mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated Mphi from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with Mphi from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect. In fact, defective TNF-alpha production appeared to be responsible for aberrant expression of the other cytokines because this defect was the first to be expressed, and treatment with exogenous TNF-alpha reduced the extent of defective IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did not correct defective proinflammatory cytokine production, IL-10 did not appear to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha production in Mphi from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that Mphi from the three normal strains studied here maintain a precise inverse relationship between levels of TNF-alpha and IL-10, a relationship not seen in Mphi from lupus-prone strains. These findings reveal shared elements of cytokine dysregulation in the two principal animal models of multigenic lupus, and suggest that the study of Mphi (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.
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PMID:Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1 lupus-prone mice. 954 4

The immunoregulating effect of Interleukin-1-receptor antagonist (IL-1ra) in lupus-like NZB/W F1 mice was investigated to find possible approach to prevent lupus nephritis. 12 female NZB/W F1 mice of 13 weeks were randomly divided into 2 groups. Each mouse in the treated group was intraperitoneally injected with IL-1ra once every 2 weeks for 3 times at the dosage of 100 micrograms each time, while the control group was given injection of 0.1 ml normal saline. All the mice were killed at the age of 9 months and the immunologic function was examined. Results showed that this dosage could not completely prevent the development of lupus nephritis, but the renal damage was alleviated and the urine protein was decreased. Moreover, it could improve the immunofunction by significantly reducing the levels of serum IL-1 and obviously increase the activities of NK cells and IL-2 induced by ConA in mononuclear cells of spleen. There was no significant difference in the levels of serum IL-6 and TNF-alpha between the treated group and control group. It is concluded that IL-1ra has certain regulatory effect on the immunologic function of lupus-like NZB/W F1 mice.
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PMID:Study on immunoregulation by interleukin-1 receptor antagonist in NZB/W F mice. 963 78

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

Prolactin (PL) is a mammotropic neuropeptide produced by the pituitary and extrapituitary cells existing as several isoforms and belongs to the growth and lactogenic hormone family, which includes growth hormone and placental lactogens. The secretion of pituitary PL is under hypothalamic control. The cytokines IL-1, IL-2, and IL-6 also stimulate production, while IFN-gamma and endothelin-3 are inhibitory. PL exerts its effects via PL receptors (PLr) which exist as three isoforms. PL regulates reproduction, osmoregulation, and behavior and has potent immunomodulatory effects. PL is structurally related to members of the cytokine/hematopoietic family such as erythropoietin, GM-CSF, growth hormone, and IL-2 to IL-7. The PLr is a member of the cytokine/hematopoietic receptor family. Interaction of PL with PLr activates the Jak kinases which phosphorylate latent STAT proteins resulting in the activation of transcription. PL counteracts the effects of corticosteroids by enhancing Th1 cellular responses. Perturbations of PL physiology have significant immunologic effects. Hypoprolactinemia impairs immune function while hyperprolactinemia enhances active systemic lupus erythematosus, Reiter's disease, juvenile and adult rheumatoid arthritis (RA), autoimmune thyroiditis, multiple sclerosis, and cardiac allograft rejection. PL gene polymorphisms have now been shown to be linked to RA. Thus, manipulation of PL may have significant clinical utility. Further study of the relationship of the PL/PLr complex, other hormones, and the immune system will provide further insights into the potential therapeutic utility of this complex in immune diseases.
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PMID:Prolactin and neuroimmunomodulation: in vitro and in vivo observations. 1041

Dysfunctional leukocyte-endothelial interactions are thought to play a key role in systemic lupus erythematosus pathogenesis. We questioned the importance of TNF-alpha and IL-1 for endothelial activation in MRL/lpr lupus-prone mice. Endothelial ICAM-1 and VCAM-1 expression increased significantly with disease evolution in kidney, heart, and brain, as shown by i.v. injected radiolabeled Ab uptake. Lung endothelial VCAM-1 also increased, while lung endothelial ICAM-1 did not rise above a high basal level. Immunoassays showed a significantly raised circulating level of TNF-alpha by 14 wk, with levels of circulating IL-1alpha and IL-1beta being additionally raised by 20 wk. With 14-wk-old MRL/lpr, anti-TNF-alpha antiserum inhibited expression of ICAM-1 and VCAM-1 by endothelial cells cultured with sera in vitro, and uptake of anti-ICAM-1 and anti-VCAM-1 mAb in lung, kidney, brain, and heart in vivo. In contrast, both anti-TNF-alpha and anti-IL-1 antisera were required for maximal inhibition in vitro and in vivo at 20 wk. These data indicate that TNF-alpha is largely responsible for the early up-regulation of endothelial ICAM-1 and VCAM-1, but that IL-1 enhances expression in late disease. Our observations provide novel insights of possible relevance to understanding endothelial activation in systemic lupus erythematosus, and highlight an approach that can be extended to dissecting other chronic inflammatory diseases.
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PMID:TNF-alpha and IL-1 sequentially induce endothelial ICAM-1 and VCAM-1 expression in MRL/lpr lupus-prone mice. 1049 Oct 2

Depositions of immune-complexes are responsible for many of the pathological features of systemic lupus erythematosus (SLE). For example, immune-complex-induced tissue damage in glomerulonephritis has been shown to be mediated, at least in part, by interleukin (IL)-1. Inappropriate production or function of IL-1 may therefore contribute to disease manifestations in SLE. We investigated lipopolysaccharide (LPS)- and adherent IgG-stimulated release of IL-1beta, IL-1 receptor antagonist (IL-1ra) and IL-10, a potent modulator of IL-1, by blood mononuclear cells from patients with SLE. Mediator production was measured as ng cytokines/10(6) monocytes and compared with clinical parameters. Release of IL-1beta was only detectable in LPS-stimulated cultures and substantially reduced in patients with both active and inactive disease (P < 0.001). LPS-stimulated IL-1ra release was normal and the IL-1ra/IL-1beta ratio was therefore increased (P < 0.05) and correlated inversely to prednisolone dosage (P = 0.009). IgG-stimulated release of IL-1ra was reduced in patients with active disease compared to those with inactive disease and controls (P = 0.002). IL-10 release was similar in patients and controls. We conclude that monocytes from patients with active SLE are deficient in Fc gamma-R-mediated production of IL-1ra, whereas LPS-stimulated IL-1beta release by SLE monocytes is reduced regardless of disease activity. The former may contribute to immune-complex-mediated tissue damage in SLE.
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PMID:Production of IL-1beta, IL-1 receptor antagonist and IL-10 by mononuclear cells from patients with SLE. 1052 99


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