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)

SK&F 105685 (N,N-Dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in animal models of autoimmune diseases such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis in the Lewis rat and lupus-like disease in the MRL mouse. The effect of SK&F 105685 on the proliferation of rat lymphoid cells was examined in vitro. The compound inhibited the proliferative response of spleen, thymus and lymph node cells to the mitogen concanavalin A (Con A) in a dose-dependent manner but had little or no effect on the mitogenic response of peripheral blood lymphocytes. Although less potent than cyclosporin A, SK&F 105685 was able to inhibit the proliferation of spleen cells stimulated with PMA and ionomycin or the mitogens phytohemagglutinin (PHA), Con A and pokeweed mitogen (PWM). Relatively early event(s) in cell proliferation were affected by SK&F 105685 since delaying addition of the drug by 24 to 48 hours after Con A stimulation of rat spleen cells resulted in reduced levels of suppression. The mode of action of SK&F 105685 appeared to differ from that of cyclosporin A or rapamycin. Unlike cyclosporin A, SK&F 105685 did not affect IL-2 production by Con A-stimulated spleen cells or the IL-2-producing Jurkat cell line, but, like rapamycin, the compound significantly reduced the IL-2-induced proliferation of rat ConA blasts. These results suggest that inhibition of lymphocyte proliferation by SK&F 105685 may require the activity of an intermediate effector cell(s) present in susceptible populations such as cells from the spleen, thymus, lymph nodes and Con A blast preparations but absent or present in low numbers in resistant populations such as peripheral blood cells. Indomethacin and NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of nitric oxide synthase, were both unable to relieve SK&F 105685-induced suppression of splenic Con A responses thereby ruling out a role for the production of prostaglandins or nitric oxide by macrophages as an intermediate in drug-mediated suppression. In summary, SK&F 105685 was unable to inhibit lymphoproliferative responses by a mechanism distinct from that of cyclosporin A or rapamycin and which appears to involve regulation of cellular interactions rather than a direct effect on responding lymphocytes.
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PMID:Inhibition of lymphoproliferative responses by SK&F 105685, a novel anti-arthritic agent. 166 43

Peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) are hyporesponsive in vitro. In order to study the role of mononuclear phagocytes (m phag) in regulating the in vitro responses of autologous lymphocytes, the MNC from 16 SLE patients (eight active, eight inactive) and 14 healthy controls were stimulated in vitro with PHA or dsDNA. The proliferative response to PHA was tested by 3H-thymidine incorporation on day 4 and the response to dsDNA using a specific haemolytic plaque assay. Indomethacin, an inhibitor of prostaglandin (PG) synthesis by m phag, was added into the cultures to test the presence of suppressive m phag acting through a PG-mediated pathway. Indomethacin augmented the proliferative response to PHA in active SLE cultures and not in inactive SLE or controls. In six of 13 SLE cultures, dsDNA totally or partly suppressed anti-dsDNA plaque-forming cell (PFC) generation. Indomethacin restored or enhanced the PFC response to dsDNA in active SLE and not in inactive SLE or controls. M phag depletion by plastic adherence prevented the effects of indomethacin. These results show that m phage exerting a suppressive activity on PHA-induced lymphocyte proliferation and on anti-dsDNA antibody production are found in cultures from active SLE and generally not in inactive SLE or healthy individuals. PHA being primarily a T-cell stimulator, the m phag suppressive activity observed in PHA-stimulated cultures is exerted on T cells. On the other hand, in two active SLE cultures depleted of T cells by OKT3 antibody, indomethacin still could enhance the PFC response to dsDNA, showing that in vitro suppressive m phag can act directly on B cells from patients with active SLE.
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PMID:Mononuclear phagocytes from patients with active systemic lupus erythematosus down-regulate the specific in vitro reactivity of autologous lymphocytes to double-stranded DNA. 329 51

Highly purified and cloned preparations of interleukin-1 (IL-1) were found to antagonize the capacity of erythropoietin (Epo) to stimulate the proliferation of mouse spleen and bone marrow erythroid precursor cells (EPC) in culture. Cloned murine IL-1 and purified and cloned human IL-1 alpha and IL-1 beta were approximately equipotent in this assay. IL-1 inhibited the proliferation response of EPC even when added as long as 17 h after Epo, suggesting that IL-1 does not affect binding of Epo to receptors or biochemical events following shortly thereafter. Indomethacin did not influence the inhibitory effect of IL-1 on Epo-induced proliferation, and PGE2 had no demonstrable effect on the process. Tumor-necrosis factor-alpha and interferons beta 1, and gamma did not affect Epo-induced proliferation. It is suggested that IL-1 mediated antagonism of the effects of Epo on erythroid precursors is a factor in the pathogenesis of many types of hypoplastic anaemia, including those associated with infections, rheumatoid arthritis and systemic lupus erythematosus, giant-cell arteritis, graft-versus-host disease and disorders associated with lymphocyte-mediated suppression of erythropoiesis.
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PMID:Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. 349 70

Addition of prostaglandin E2 (PGE2) to blood mononuclear cell cultures containing pokeweed mitogen (PWM) enhances plasma cell (PC) differentiation measured by intracytoplasmic immunoglobulin 7 days later. T-cell mitogenesis to concanavalin A is inhibited using the same concentrations of PGE2. PGE2 failed to enhance the PC differentiation of lymphocytes from patients with systemic lupus erythematosus (SLE). Indomethacin, on the other hand, either had no effect or suppressed PC differentiation. The data is discussed in terms of the effect of PGE2 on human suppressor T-cell function.
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PMID:Prostaglandin E2-mediated enhancement of human plasma cell differentiation. 621 Jun 27

The aim of this study was to define as possible abnormality of interleukin 2 (IL2) production by PHA-stimulated peripheral blood lymphocytes (PBL) in systemic lupus erythematosus (SLE). Thirty-four SLE PBL samples were stimulated to produce IL2 and compared with PBL from healthy (age- and sex-matched) controls. A significant defect in IL2 production was observed in SLE patients. This defect was not restricted to corticosteroid-treated patients and was not correlated with the presence of lymphotoxic antibodies or with clinical disease activity. Although 5-day responsiveness to phytohaemagglutinin (PHA) decreased in SLE, the SLE PHA-blasts responded as well as control blasts to semipurified IL2, suggesting that the receptor for IL2 was normally expressed on SLE blasts. In 9 cases, the effect of addition of indomethacin (2 micrograms/ml) or of an optimal amount of IL1 on PHA-induced IL2 production was studied. Indomethacin increased (22%) the IL2 yield of healthy individual PBL. In SLE, indomethacin (but not IL1) was able to completely restore (41% increase) the IL2 production of lectin-stimulated PBL (P less than 0.01). These data suggest that, in SLE, the inhibition of IL2 production is mediated by prostaglandin, possibly produced by monocytes.
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PMID:Impaired IL2 production by lymphocytes of patients with systemic lupus erythematosus. 633 9

The effects of indomethacin on urinary protein excretion, levels of serum albumin and renal function were studied prospectively in six patients with systemic lupus erythematosus (SLE) and refractory nephrotic syndrome due to lupus nephritis. Two had membranoproliferative glomerulonephritis, two had diffuse proliferative glomerulonephritis, and one each had mesangioproliferative and membranous glomerulonephritis. All experienced a considerable reduction in urinary protein excretion and an increase in serum albumin. Indomethacin was discontinued in two patients because of side effects, and proteinuria recurred to pretreatment levels. The decrease of proteinuria continued during long-term treatment in three patients. Indomethacin did not cause a permanent decline in renal function. Our results suggest that therapy with indomethacin may be beneficial for the treatment of refractory nephrotic syndrome in selected SLE patients. However, because of potential side effects the administration of indomethacin should be monitored closely.
Lupus 1993 Feb
PMID:Refractory nephrotic syndrome in lupus nephritis: favorable response to indomethacin therapy. 848 64

Systemic lupus erythematosus (SLE) is characterized by inflammatory and dysregulatory immune responses including overactive B cells, overproduction of proinflammatory cytokines, and T cell hyperactivity. PGE(2) modulates a variety of immune processes at sites of inflammation, including production of inflammatory cytokines. However, the role of PGE(2) in dysregulatory inflammatory and immune responses in lupus remains unclear. We investigated whether PGE(2) mediates production of inflammatory cytokines in pristane-induced lupus BALB/c mice. Our results showed that levels of serum and BAL PGE(2) and LPS-stimulated production of PGE(2) by peritoneal macrophages were remarkably increased in pristane-induced lupus mice compared to healthy controls. Exogenous PGE(2) enhanced production of IL-6, IL-10, and NO but decreased TNF-alpha by macrophages and augmented IFN-gamma, IL-6, and IL-10 by splenocytes from pristane-induced lupus mice compared to healthy controls. Exogenous PGE(2) also enhanced production of IFN-gamma, IL-6, and IL-10 by thymocytes from pristane-induced lupus mice. Indomethacin (Indo), a PGE(2) synthesis inhibitor, greatly inhibited LPS-induced production of IL-6 and IL-10 by macrophages from pristane-induced lupus mice, while enhanced TNF-alpha. Indo remarkably inhibited Con A-increased production of IFN-gamma, IL-6, and IL-10 by splenocytes and thymocytes from pristane-induced lupus mice. Therefore, our findings suggest that endogenous PGE(2) may mediate dysregulation of production of proinflammatory cytokines, such as IL-6, IL-10, and IFN-gamma, and NO in pristane-induced lupus mice.
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PMID:Prostaglandin E2-mediated dysregulation of proinflammatory cytokine production in pristane-induced lupus mice. 1844 9