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)

Mesangial cells from MRL/lpr mice, a model of lupus, overproduce nitric oxide (NO) compared to controls. J series prostaglandins (PG) and thiazolidinediones block LPS stimulation of NO production via the activation of peroxisome proliferator-activator receptor-gamma (PPAR-gamma) in macrophages but utilize an alternative mechanism in microglial cells. We investigated the mechanism by which PGJ(2) inhibits NO production in LPS/IFN-gamma-stimulated MRL/lpr mesangial cells. Our results demonstrated that LPS/IFN-gamma addition to MRL/lpr mesangial cells stimulated iNOS activation, expression of p-38 kinase and p44/42 MAPK, and NF-kappaB translocation to the nucleus. Both pioglitazone, a specific PPAR-gamma agonist, and PGJ(2) blocked NO production, iNOS protein expression, and iNOS mRNA transcription. PGJ(2) failed to inhibit nuclear NF-kappaB translocation or p44/42 MAPK or p-38 kinase induction in stimulated mesangial cells. These data suggest that PGJ(2) blocks iNOS expression and subsequent NO production in mesangial cells via a PPAR-gamma-mediated mechanism either by interfering with NF-kappaB transcriptional activity or by an NF-kappaB-independent mechanism.
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PMID:Prostaglandin J(2) inhibition of mesangial cell iNOS expression. 1123 57

Overexpression of inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus glomerulonephritis. Mycophenolate mofetil (MMF), a novel immunosuppressive agent, is currently used in organ transplantation and under evaluation for treatment of autoimmune disorders. Mycophenolic acid, the active metabolite of MMF, has been shown to suppress cytokine-induced nitric oxide production in vitro. The aim of this study was to evaluate the effect of MMF on the expression of renal cortical iNOS mRNA and protection against glomerulonephritis in MRL/lpr mice. Three-month-old MRL/lpr mice (n = 6) displaying clinical symptoms of glomerulonephritis were treated for 3 months with MMF (90 mg/kg/day) dissolved in a vehicle. Controls were age- and sex-matched mice (n = 6) that received the vehicle alone. By reverse-transcription competitive polymerase chain reaction, we found that the renal cortical iNOS/beta-actin mRNA ratio was reduced by 30.8% (P <.05) in MMF-treated mice. Furthermore, MMF significantly reduced urinary nitrite production and degree of glomerulosclerosis. The glomerular volume was reduced by 17.5% (P <.001). Proteinuria was also significantly reduced in the MMF-treated group. However, by electrophoretic mobility shift assay, the nuclear binding of nuclear factor-kappaB (NF-kappaB) was not affected by MMF treatment. We conclude that in addition to its immunosuppressive action, MMF may reduce renal cortical iNOS mRNA expression and diminish glomerulosclerosis in MRL/lpr mice independent of modulation of the NF-kappaB pathway.
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PMID:Mycophenolate mofetil reduces renal cortical inducible nitric oxide synthase mRNA expression and diminishes glomerulosclerosis in MRL/lpr mice. 1143 30

Receptors for prolactin (PRL-R) are expressed in normal leukocytes from rat and man. PRL signals through PRL-R associated Janus tyrosine kinase (Jak)-2 and signal transducers and activators of transcription (Stat). In addition, in human leukocytes PRL also activates the p38 MAP kinase pathway. PRL, at physiological concentrations, stimulates the expression of the interferon regulatory factor (IRF)-1 gene in rat spleen and bone marrow cells. In man, genes induced by PRL include several members of the 'suppressors of cytokine signaling' (SOCS) family and inducible nitric oxide synthase (iNOS; in mononuclear cells and in granulocytes) and IRF-1 (in granulocytes). Thus, in normal leukocytes, PRL induces the expression of several genes relevant to innate and acquired immune responses. Sex hormones, such as estrogen and PRL, have been implicated in the pathogenesis of murine and human SLE. Also defective signaling in leukocytes is a feature of the disease. What the origin is of aberrant signaling processes in SLE lymphocytes and how they relate to tolerance breakdown and immunopathology is still unknown. It is not unlikely that PRL is a player at some level. The exact contribution of PRL to immune responses in normal subjects and in SLE patients is not known. Further work should also indicate whether PRL might contribute to the onset or progression of the disease and assess the possible benefits of manipulating PRL concentrations in patients.
Lupus 2001
PMID:Effects of prolactin on signal transduction and gene expression: possible relevance for systemic lupus erythematosus. 1172 98

Mycophenolate mofetil (MMF), an immunosuppressive drug commonly used in organ transplantation, is increasingly being used to treat autoimmune diseases including systemic lupus erythematosus (SLE). Excessive production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus nephritis. We evaluated the effect of MMF on the severity of nephritis and the production of NO in lupus-prone MRL/lpr mice. Eight-week-old female MRL/lpr mice (n = 20) were treated with MMF (100 mg/kg/day) by oral gavage for 12 weeks. Control mice (n = 20) received vehicle on the same schedule. The mice were killed after 12 weeks of treatment. Treatment with MMF significantly decreased the amount of proteinuria, prolonged survival and reduced the histological severity of glomerulonephritis. Urinary nitrite/nitrate excretion in the MMF-treated mice was significantly reduced during the first 8 weeks of treatment. However, by the end of the 12 weeks' treatment period, there was no significant difference between vehicle and MMF-treated mice in terms of urinary nitrite/nitrate excretion, intra-renal production of NO, expression of iNOS protein and induction of iNOS mRNA. We conclude that MMF is effective in attenuating the severity of nephritis in MRL/lpr mice. The beneficial effects of MMF on lupus nephritis during the early phase of the disease might be partly attributed to the inhibition of NO production. The inhibitory effect of MMF on NO production diminishes as the disease progresses. MMF probably has additional, as yet undefined mode of actions to fully account for its beneficial effects on lupus nephritis.
Lupus 2002
PMID:Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice. 1219 81

Prostaglandin E(2) (PGE(2)) can have pro- or anti-inflammatory effects, depending on engagement of different PGE(2) receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon-gamma in combination with EP subtype-specific agonists. Tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 production was tested by enzyme-linked immunosorbent assay (culture supernatant) and flow cytometry. TNF-alpha mRNA levels also were examined. High levels of EPs (EP4/2>EP1>EP3), iNOS, and COX-2 mRNA were expressed in peritoneal macrophages from pristane-treated but not untreated or thioglycolate-treated mice (RT-PCR). TNF-alpha production was inhibited 50-70% at 2-24 h by EP4/2 agonists, whereas IL-6 was enhanced up to approximately 220%. TNF-alpha inhibition is mediated partly via the protein kinase A pathway and partly via IL-6. Intracellular TNF-alpha staining was inhibited 20% by EP4/2 agonists. TNF-alpha mRNA levels were inhibited 50-70% at 2-24 h, indicating that TNF-alpha inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF-alpha production. PGE(2) can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF-alpha and IL-6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.
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PMID:Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-alpha and IL-6 production. 1507 56

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumour necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhibit the proliferation of immunocytes and the activation of natural killer cells. Regarding the above facts and in view of their safety and inexpensiveness, statins may prove invaluable in the treatment of a multiplicity of dermatologic disorders, especially those characterized by ingress of activated leucocytes into the skin, such as alopecia areata, vitiligo, lichen planus, subacute cutaneous lupus erythematosus, erythema multiforme, psoriasis, bullous pemphigoid, systemic sclerosis, mycosis fungoides, toxic epidermal necrolysis and Behcet's disease.
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PMID:Statins: novel additions to the dermatologic arsenal? 1518 18

There is accumulating evidence that haem oxygenase (HO)-1 plays a protective role in various disorders. The beneficial efficacy of HO-1 induction therapy has been shown in renal diseases such as glomerulonephritis, interstitial nephritis and drug induced nephrotoxicity. However, involvement of HO-1 in the development of autoimmune renal diseases remains uncertain. To assess the clinical efficacy of HO-1 induction therapy for lupus glomerulonephritis, MRL/lpr mice were intraperitoneally injected with 100 micromol/kg hemin, a potent HO-1 inducer, or PBS as controls, once a week from 6 weeks of age to 21-24 weeks-old. We found that treatment with hemin led to a significant reduction of proteinuria and remarkable amelioration of glomerular lesions accompanied by decreased immune depositions. In addition, the circulating IgG anti-double-stranded DNA antibody level was significantly decreased in hemin treated mice when compared with controls. A single intraperitoneal injection with hemin resulted in reduction of inducible nitric oxide synthase expression in the kidney and spleen, and serum interferon-gamma level. Our results suggest that HO-1 induction therapy ameliorates lupus nephritis by suppressing nitric oxide (NO) dependent inflammatory responses and attenuating production of pathogenic autoantibodies.
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PMID:Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibody. 1549 32

Monoclonal ribosomal P protein antibody (anti-P mAb) may bind to the cell surface, penetrate into cells, and induce apoptosis of Jurkat T cells. Recently, modulation of cytokines has been considered to be important in the pathogenesis of systemic lupus erythematous (SLE). In this study, effects of anti-P mAbs (9B6) on gene expression of cytokines, apoptosis, and reactive oxygen species in murine macrophage RAW 264.7 were analyzed by RT-PCR and ELISA and those on IL-12 promoter activity was determined in an IL-12p40 promoter-reporter gene transfected cell line RAW (IL-12p40-SEAP). After treating LPS-activated RAW 264.7 with 9B6 for 6 or 24 h, the levels of mRNA and protein expression of IL-12, TNF-alpha, and iNOS were significantly inhibited by 25%, 16%, and 13%, respectively. The IL-12 promoter activity of RAW (IL-12p40-SEAP) was also inhibited by 13-22%. However, inhibitory effects were not observed in cells pre-treated with IgG1 for 1 h. The productions of IL-10 in LPS-activated RAW 264.7 and human macrophages were potentiated by 9B6 up to 65% and 51%, respectively. Since anti-P Abs inhibit productions of IL-12 and TNF-alpha and enhance IL-10 production in macrophages, these autoantibodies may augment Th2 responses and amplify lupus manifestations by causing immunological polarity and lymphocyte dysfunction.
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PMID:Monoclonal ribosomal P autoantibody inhibits the expression and release of IL-12, TNF-alpha and iNOS in activated RAW macrophage cell line. 1582 6

Nitric oxide (NO) production increases with age in the lupus-prone MRL/lpr mouse, paralleling disease activity. One mechanism for excess NO production in MRL/lpr mice may be a defect in down-regulatory mechanisms of the iNOS pathway. A potential modulator of NO is the nuclear hormone receptor peroxisome proliferation activated receptor gamma (PPARgamma). We demonstrate that renal PPARgamma protein expression was altered as disease progressed in MRL/lpr mice, which paralleled increased iNOS protein expression. Additionally, MRL/lpr-derived primary mesangial cells expressed less PPARgamma than BALB/c mesangial cells and produced more NO in response to LPS and IFNgamma. Furthermore, PPARgamma activity was reduced in mesangial cells following exposure to inflammatory mediators. This activity was restored with the addition of a NOS enzyme inhibitor. These results indicate that the activation of inflammatory pathways may lead to reduced activity and expression of PPARgamma, further exacerbating the disease state.
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PMID:Inflammatory modulation of PPAR gamma expression and activity. 1630 34

Lupus erythematosus (LE) is an autoimmune disease which can be triggered by environmental factors such as solar irradiation. It has long been observed that especially ultraviolet (UV) exposure can induce and exacerbate skin lesions in patients with this disease. However, despite the frequency of photosensitivity in LE, the mechanisms by which UV irradiation activates autoimmune responses is only now becoming increasingly unfolded by advanced molecular and cellular biological investigations. Phototesting, according to a standardized protocol with UVA and UVB irradiation has proven to be a valid model to study photosensitivity in various subtypes of LE and to evaluate the underlying pathomechanisms of this disease. Detailed analysis of the molecular events that govern lesion formation in experimentally photoprovoced LE showed increased accumulation of apoptotic keratinocytes and impaired expression of the inducible nitric oxide synthase (iNOS). In the near future, gene expression profiling and proteomics will further increase our knowledge on the complexity of the "UV response" in LE. This review summarizes the current understanding of the clinical and molecular mechanisms that initiate photosensitivity in this disease.
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PMID:Photosensitivity in lupus erythematosus. 1637 57


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