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

TWEAK is a newly identified member of the Tumor Necrosis Factor (TNF) family of proteins which are involved in many immunoinflammatory mechanisms. The putative role of TWEAK in inflammation was analyzed in mice treated with lipopolysaccharide (LPS), a strong inducer of the immuno-inflammatory responses. TWEAK mRNA rapidly disappeared in all the tissues tested. Analysis of LPS-treated thioglycolate-elicited peritoneal macrophages revealed that the rapid loss of TWEAK mRNA was due to its active destabilization. In chronic pathologies like autoimmune hemolytic anemia in the NZB mouse strain or systemic lupus erythematosus (SLE) in the BXSB mouse strain, TWEAK mRNA was shown to be reduced concomitantly to the development of chronic autoimmune diseases. These results demonstrated that TWEAK mRNA, contrary to TNF mRNA, is stable, ubiquitously distributed in tissues, and is down-regulated after LPS treatment or in chronic inflammation, suggesting that TWEAK could be an important factor, along with TNF, in acute and chronic inflammations.
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PMID:Down-regulated expression of TWEAK mRNA in acute and chronic inflammatory pathologies. 1111 33

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-alpha and IL-1beta. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a "negative" acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that high-density lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-alpha and IL-1beta production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis.
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PMID:Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. 1129 Jun 1

The aim of this study was to evaluate the effects of the immunomodulating drug mycophenolic acid (MPA) on splenocytes in an animal model of systemic lupus erythematosus (SLE), using MRLlpr/lpr mice. MPA reversibly inhibits inosine 5'-monophosphate dehydrogenase, an enzyme involved in the de novo guanosine synthesis. Splenocytes were treated with MPA (at 1 or 10 microM), and stimulated with either lipopolysaccharide (LPS; 10 microg/ml) or concanavalin A (ConA; 1.25 microg/ml). In blocking experiments, guanosine (100 microM) was added to the cultures to inhibit the effects of MPA. Lymphocyte proliferation, enumeration of immunoglobulin producing cells (using ELISPOT) and quantification of anti-double-stranded (ds) DNA antibodies, IFN-gamma and IL-10 (by ELISA) in supernatants were performed. In addition, cell viability was evaluated using propidium iodide and flow cytometry. We found that MPA-treated splenocytes had dramatically decreased mitogen-induced proliferation and number of immunoglobulin producing cells, down-regulated production of IFN-gamma, IL-10 and IgM anti-dsDNA antibodies. The viability of MPA-treated cells was also decreased. All of the effect modulated by MPA could be neutralized by the addition of guanosine. We conclude that MPA has potent immunomodulating effects on both B and T lymphocytes, modulating not only proliferation, but also the production of cytokines, immunoglobulins and autoantibodies.
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PMID:Inosine monophosphate dehydrogenase (IMPDH) inhibition in vitro suppresses lymphocyte proliferation and the production of immunoglobulins, autoantibodies and cytokines in splenocytes from MRLlpr/lpr mice. 1147 13

Acute, lethal graft-versus-host disease (GvHD) develops in B6D2F1 hybrid recipients of wild-type, C57BL/6, parental strain grafts; however, when interferon-gamma (IFN-gamma) gene knockout (gko) donors are used, the disease is prolonged and associated with a higher level of engraftment, particularly of T cells. Lesions containing large, mixed cellular infiltrates develop in the skin, liver, pancreas, salivary gland, lung and kidney. In our current study, we wished to determine whether GvHD features a preponderance of T helper 2 (Th2) cytokines in the absence of donor-derived IFN-gamma, and whether autoantibody production, commonly associated with chronic GvHD, also occurs. Because mitogen responsiveness is consistently suppressed in mice with acute GvHD, we wished to measure this response in recipients of IFN-gamma gko grafts. Our findings indicate that spleen cells from the latter produce interleukin (IL)-4, IL-5 and IL-13 in culture, but respond poorly to concanavalin A (Con A) and lipopolysaccharide (LPS). Their sera contain anti-nuclear antibodies (ANA), some of which are specific for double-stranded (ds)DNA and are predominantly immunoglobulin (Ig)M and IgG1. We also noted the presence of numerous eosinophils in the infiltrates developing within the target organs. In some respects, this syndrome bears resemblance to both systemic lupus erythematosus (SLE) and chronic GvHD. However, histological evidence of glomerulonephritis is lacking and proteinuria fails to develop in recipients of IFN-gamma gko grafts, suggesting that IFN-gamma may be necessary for the development of lupus nephritis. On a broader scope, our findings underscore the importance of IFN-gamma in the pathogenetic mechanism of GvHD, and demonstrate that the absence of this cytokine promotes the development of chronic GvHD and autoimmunity.
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PMID:Murine graft-versus-host disease induced using interferon-gamma-deficient grafts features antibodies to double-stranded DNA, T helper 2-type cytokines and hypereosinophilia. 1184 16

Mycophenolic acid (MPA) inhibits reversibly inosine 5(')-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA's immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-gamma. Cytokine, NO(2)(-), and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE.
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PMID:Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages. 1238 54

Polymorphonuclear leukocytes (PMN) play an important role in eradicating bacterial infections. To test if PMN of patients with systemic lupus erythematosus (SLE) have defective capacity to produce IL-12, IL-12 p35 gene transcription and p70 excretion by PMN were evaluated in SLE patients and normal subjects. Peripheral blood PMN from 25 patients with active SLE and 25 normal individuals were stimulated with lipopolysaccharide (LPS, 100ng/mL) in the presence or absence of recombinant interferon (IFN)-gamma (5-200IU/mL). The IL-12 p35 gene transcripts were analyzed by reverse transcription - polymerase chain reaction (RT-PCR) and the IL-12 p70 in culture supenatants was quantified by enzyme immunoassay (EIA). At the 6th hour of stimulation, IL-12 expression in PMN of SLE patients was less prominent than that of the normal controls. The IL-12 was produced by normal PMN on LPS stimulation in the absence of IFN-gamma. IFN-gamma enhanced the IL-12 production by normal PMN stimulated with LPS, but it inhibited the IL-12 production in PMN from active lupus patients in the presence of LPS. Analysis with PCR using the same primers on the chromosomal DNA showed that p35 gene was intact in SLE patients. These results have suggested that SLE-PMN may have defect in IL-12 expression and the defect may be exaggerated in the presence of IFN-gamma which normally stimulates IL-12 production. This may account for increased susceptibility to multiple infections in patients with active SLE.
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PMID:Decreased IL-12 production by polymorphonuclear leukocytes in patients with active systemic lupus erythematosus. 1247 78

Recent studies indicate that normal B cells can be primed to differentiate into two distinct cytokine-secreting effector subsets, Be1 and Be2. The aim of this study was to analyse, for the first time, Be1 and Be2 cells at the single cell level in SLE patients using the recently developed technique of flow cytometry for intracellular cytokines. Peripheral blood mononuclear cells (PBMC) from SLE patients and age- and sex-matched normal controls were cultured for 24 h in the presence or absence of phorbal myristate acetate and ionomycin (PMA/I) or lipopolysaccharide (LPS). The production of type I (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-6, IL-10, IL-13) cytokines by B cells (and IL-10 production by fractionated CD5+ and CD5- B cells) was investigated using an intracellular cytokine staining technique and flow cytometry. In the absence of PMA/I stimulation, the percentage of B cells from SLE patients was significantly lower than those of normal subjects and significantly more SLE B cells spontaneously produced IL-10 than controls. Moreover, CD5+ B cells from SLE patients were enriched for cells with signs of previous in vivo activation and for high levels of IL-10 production. A significant positive correlation was observed between the percentage of IL-10- and IL-6-producing PMA/I-stimulated B cells in SLE patients, but not in controls. There were no significant differences in the production of other cytokines by B cells of SLE patients and normal subjects. In conclusion, a general alteration of type 1 and type 2 cytokine production by B cells is not observed in SLE patients. The role of B cell cytokines in the pathogenesis of SLE appears to be exerted by elevated secretion of in vivo IL-10, which may play an important role in the immune dysregulation observed in SLE patients. Moreover, the cross regulation of IL-10 and IL-6 is disrupted in SLE patients.
Lupus 2003
PMID:Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells. 1276 98

Inadequate immune response to infectious danger may contribute to the pathogenesis of systemic autoimmune diseases, e.g., systemic lupus erythematosus. To test this hypothesis, we studied innate responses of prediseased lupus-prone Palmerston North (PN) mice to lipopolysaccharide (LPS), bacterial DNA, and synthetic CpG oligonucleotides. LPS and bacterial DNA/CpG oligodeoxyribonucleotides (ODNs) drove PN splenocytes into the cell cycle and protected B cells against spontaneous apoptosis, as in control lupus-free DBA-1 mice. LPS induced significantly higher IL-6 production in PN than in control splenocytes. In contrast, in PN splenocytes bacterial DNA and CpG ODNs induced approximately four- to sixfold lower IL-12p40 and approximately twofold lower IL-6 secretion than controls. This reduction in cytokine secretion in PN mice was not due to delayed kinetics but was related to significantly higher constitutive and CpG-inducible IL-10 secretion. Neutralizing anti-IL-10 antibodies almost completely restored PN IL-6 and IL-12p40 secretion to DBA-1 levels, whereas exogenous IL-10 inhibited in vitro IL-6 and IL-12p40 production in DBA-1 mice. Importantly, treatment with either IL-10 or anti-IL-10 antibody did not modulate CpG-induced cell cycle entry and apoptosis protection in either strain. In conclusion, lupus-prone PN mice show abnormal innate responses through their pattern-recognition TLR9 receptors, characterized by higher inducible IL-10 and lower IL-12p40 and IL-6 secretion, thus implying that response to infectious danger in PN mice is inappropriate and may be linked to lupus pathogenesis.
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PMID:Innate immune responses in lupus-prone Palmerston North mice: differential responses to LPS and bacterial DNA/CpG oligonucleotides. 1279 42

The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the pathogenesis of diseases associated with immunoactivation and inflammation. Consequently, blockage of IL-18 bioactivity by use of IL-18 binding protein (IL-18 BP) is likely a promising therapeutic concept. In the present study, we investigated immunomodulatory activities of IL-18 BPa:Fc in human whole blood cultures. We report that IL-18 BPa:Fc (200 ng/mL) significantly inhibited lipopolysaccharide (LPS, 10 ng/mL)/IL-12 (5 ng/mL)-induced release of interferon-gamma (IFNgamma) and matrix metalloproteinase-9 (MMP-9) from whole blood cultures of healthy donors. Notably, IL-18 BPa:Fc (200 ng/mL) further reinforced dexamethasone (5 nM)- or mycophenolic acid (2 microM)-mediated reduction of LPS/IL-12-induced IFNgamma production by an additional 50.5 or 49.9%, respectively. To investigate effects of IL-18 BP:Fc in the context of autoimmune diseases, experiments were performed with whole blood obtained from patients with systemic lupus erythematosus or Wegener's granulomatosis undergoing immunosuppressive therapy. After ex vivo stimulation with LPS (10 ng/mL), production of IFNgamma and MMP-9 was determined. Both mediators likely contribute to renal inflammation frequently seen in these diseases. In accord with the aforementioned data, LPS (10 ng/mL)-induced IFNgamma was significantly reduced by coincubation with IL-18 BPa:Fc at 200 ng/mL. IL-18 BPa:Fc also inhibited production of MMP-9. The present data demonstrate that IL-18 BPa:Fc has the potential to amplify anti-inflammatory actions of immunosuppressive drugs, and thus may prove to be a valuable novel pharmacological component in the treatment of human autoimmune diseases.
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PMID:IL-18BPa:Fc cooperates with immunosuppressive drugs in human whole blood. 1290 50

TLR4 and RP105 are unique members of the Toll-like receptor (TLR) family molecules. They are associated with small molecules called MD-2 and MD-1, respectively, to form heterodimers (TLR4/MD-2 and RP105/MD-1) and function as recognition/signaling molecules of lipopolysaccharide (LPS), a membrane component of Gram-negative bacteria. Analysis of transfectant cell lines and gene-targeted mice revealed that both MD-2 and MD-1 are involved in the recognition of LPS as well as in the regulation of intracellular distribution and the surface expression of TLR4 and RP105, respectively. Since RP105 or MD-1-deficient mice show a reduced but not complete lack of LPS responsiveness, there may be functional associations between TLR4/MD-2 and RP105/MD-1. In addition, there was an increased frequency of RP105-negative B-lymphocytes in the peripheral blood in several rheumatic diseases, such as systemic lupus erythematosus, suggesting the involvement of RP105 in the pathophysiology of autoimmunity. Further analysis of the structure and function of TLR4/MD-2 and RP105/MD-1 will provide a better understanding of the pathophysiology, and a chance to develop evidence-based treatments for septic shock syndrome and autoimmunity.
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PMID:Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide. 1462 Jan 36


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