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)

Rap1 (Ras-proximity 1), a member of the Ras family of small guanine triphosphatases (GTPases), is activated by diverse extracellular stimuli. While Rap1 has been discovered originally as a potential Ras antagonist, accumulating evidence indicates that Rap1 per se mediates unique signals and exerts biological functions distinctly different from Ras. Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types. Recent studies (including gene-targeting analysis) have uncovered that the Rap1 signal is integrated crucially and unpredictably in the diverse aspects of comprehensive biological systems. This review summarizes the role of the Rap1 signal in developments and functions of the immune and hematopoietic systems as well as in malignancy. Importantly, Rap1 activation is tightly regulated in tissue cells, and dysregulations of the Rap1 signal in specific tissues result in certain disorders, including myeloproliferative disorders and leukemia, platelet dysfunction with defective hemostasis, leukocyte adhesion-deficiency syndrome, lupus-like systemic autoimmune disease, and T cell anergy. Many of these disorders resemble human diseases, and the Rap1 signal with its regulators may provide rational molecular targets for controlling certain human diseases including malignancy.
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PMID:Regulation of immune responses and hematopoiesis by the Rap1 signal. 1738 43

The transcription factor c-Jun regulates the expression of genes involved in proliferation and inflammation in many cell types but its role in human renal disease is largely unclear. In the current study we investigated whether c-Jun activation is associated with human renal disease and if c-Jun activation regulates pro-inflammatory and pro-fibrotic genes in renal cells. Activation of c-Jun was quantified by scoring renal expression of phosphorylated c-Jun (pc-Jun) in control human renal tissue and in biopsies from patients with various renal diseases (diabetic nephropathy, focal glomerulosclerosis, hypertension, IgA nephropathy, membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, systemic lupus erythematosus, acute rejection, and Wegener's granulomatosis); this was correlated with parameters of renal damage. Furthermore, we studied the functional role of c-Jun activation in human tubular epithelial cells (HK-2) stimulated with TGF-beta. Activated c-Jun was present in nuclei of glomerular and tubular cells in all human renal diseases, but only sporadically in controls. Across the diseases, the extent of pc-Jun expression correlated with the degree of focal glomerulosclerosis, interstitial fibrosis, cell proliferation, kidney injury molecule-1 (Kim-1) expression, macrophage accumulation, and impairment of renal function. In HK-2 cells, TGF-beta induced c-Jun activation after 1 h (+40%, p < 0.001) and 24 h (+160%, p < 0.001). The specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 abolished c-Jun phosphorylation at all time points and blunted TGF-beta- or BSA-induced procollagen-1alpha 1 and MCP-1 gene expression in HK-2 cells. We conclude that in human renal disease, the transcription factor c-Jun is activated in glomerular and tubular cells. Activation of c-Jun may be involved in the regulation of inflammation and/or fibrosis in human renal disease.
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PMID:Glomerular and tubular induction of the transcription factor c-Jun in human renal disease. 1789 46

A multitude of interferon (IFN)-inducible genes (IFIGs) are coordinately expressed in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE), emphasising the globle activating of signal pathway mediated by IFN-I in SLE. In this study, we investigated the mechanisms of expression regulation of IFIT4 (interferon induced protein with tetratricopeptide repeats 4) by IFN-alpha. We found that IFN-alpha failed in inducing IFIT4 in STAT1-negative U3A cells. Ectopic expression of STAT1, but not mutant STAT1-S727A, almost completely restored IFN-alpha2a-induced IFIT4 expression. IFN-alpha induced the expression of IFIT4 and STAT1 in THP-1 cells, and this process was significantly antagonized by the specific inhibitors of both PKCdelta and JNK or their dominant negative mutants respectively. The inhibition of JNK activity by its specific inhibitor or its dominant negative mutant suppressed both IFIT4 expression and serine phosphorylation of STAT1 but not the activation of PKCdelta, while inhibition of PKCdelta suppressed activation of IFIT4, STAT1, and JNK. Our results suggest that the induction of IFIT4 transcription by IFN-alpha depends upon sequential activation of PKCdelta, JNK and STAT1, and that the influence of PKCdelta or JNK on IFN-alpha-mediated induction of IFIT4 is dependent upon the phosphorylation of STAT1 at Ser-727. The results in our experiment provide an in vitro model of the signaling mechanisms of IFIGs regulated by IFN-alpha, that is putatively thought to occur in vivo as the one of pathogenesis of SLE.
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PMID:Sequential activation of protein kinase C delta and JNK is required for interferon-alpha-induced expression of IFIT4. 1793 93

It is shown in this study that the heparan sulfate proteoglycan agrin is overexpressed in T cells isolated from patients with the autoimmune disease systemic lupus erythematosus (SLE). Freshly isolated CD4(+) and CD8(+) subpopulations both exhibited higher expression over healthy controls, which however, gradually declined when cells were cultured in vitro. Agrin expression was induced following in vitro activation of cells via their Ag receptor, or after treatment with IFN-alpha, a cytokine shown to be pathogenic in lupus. Furthermore, serum from SLE patients with active disease was able to induce agrin expression when added to T cells from healthy donors, an increase that was partially blocked by neutralizing anti-IFN-alpha Abs. Cross-linking agrin with mAbs resulted in rapid reorganization of the actin cytoskeleton, activation of the ERK MAPK cascade, and augmentation of anti-CD3-induced proliferation and IL-10 production, indicating that agrin is a functional receptor in T cells. These results demonstrate that agrin expression in human T cells is regulated by cell activation and IFN-alpha, and may have an important function during cell activation with potential implications for autoimmunity.
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PMID:Agrin signalling contributes to cell activation and is overexpressed in T lymphocytes from lupus patients. 1802 46

We previously reported that some systemic lupus erythematosus (SLE) patients have a population of circulating memory B cells with >2-fold higher levels of CD19. We show here that the presence of CD19(hi) B cells correlates with long-term adverse outcomes. These B cells do not appear anergic, as they exhibit high basal levels of phosphorylated Syk and ERK1/2, signal transduce in response to BCR crosslinking, and can become plasma cells (PCs) in vitro. Autoreactive anti-Smith (Sm) B cells are enriched in this population and the degree of enrichment correlates with the log of the serum anti-Sm titer, arguing that they undergo clonal expansion before PC differentiation. PC differentiation may occur at sites of inflammation, as CD19(hi) B cells have elevated CXCR3 levels and chemotax in response to its ligand CXCL9. Thus, CD19(hi) B cells are precursors to anti-self PCs, and identify an SLE patient subset likely to experience poor clinical outcomes.
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PMID:A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE. 1807 20

The ShcA locus encodes 3 protein isoforms that differ in tissue specificity, subcellular localization, and function. Among these, p66Shc inhibits TCR coupling to the Ras/MAPK pathway and primes T cells to undergo apoptotic death. We have investigated the outcome of p66Shc deficiency on lymphocyte development and homeostasis. We show that p66Shc(-/-) mice develop an age-related lupus-like autoimmune disease characterized by spontaneous peripheral T- and B-cell activation and proliferation, autoantibody production, and immune complex deposition in kidney and skin, resulting in autoimmune glomerulonephritis and alopecia. p66Shc(-/-) lymphocytes display enhanced proliferation in response to antigen receptor engagement in vitro and more robust immune responses both to vaccination and to allergen sensitization in vivo. The data identify p66Shc as a negative regulator of lymphocyte activation and show that loss of this protein results in breaking of immunologic tolerance and development of systemic autoimmunity.
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PMID:The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity. 1833 75

Studies have revealed that increased expression of interferon (IFN)-inducible Ifi202 gene (encoding p202 protein) in splenic B and T cells from B6.Nba2 congenic (congenic for Nb2 locus derived from NZB mice) female mice is associated with lupus susceptibility. However, signaling pathways that regulate Ifi202 expression in immune cells remain to be elucidated. Here we report that stimulation of T cells up-regulates the Ifi202 expression. We found that steady-state levels of Ifi202 mRNA and protein were detectable in splenic T cells from NZB mice and stimulation of T cells with anti-CD3 and anti-CD28 up-regulated expression of the Ifi202 gene. Similarly, stimulation of cells of a mouse T cell hybridoma cell line (2B4.11) also activated transcription of the Ifi202 gene. Significantly, up-regulation of Ifi202 expression in stimulated T cells was inhibited by treatment of cells with SP600125, a specific inhibitor of c-Jun N-terminal kinase (JNK). Conversely, treatment of cells with anisomycin, a potent activator of the JNK and c-Jun, up-regulated Ifi202 expression. Consistent with the activation of JNK/c-Jun pathway by T cell stimulation, forced expression of c-Jun in 2B4 T cells and in mouse embryonic fibroblasts (MEFs) also up-regulated the Ifi202 expression. Furthermore, we found that stimulation of T cells increased association of the activated c-Jun to the 5'-regulatory region of the Ifi202 gene in chromatin immunoprecipitation assays (ChIPs). Together, our observations demonstrate that stimulation of T cells up-regulates the Ifi202 expression in part through the JNK/c-Jun pathway.
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PMID:Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway. 1837 89

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.
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PMID:Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. 1852 34

Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women of reproductive age. The disease is characterized by exaggerated T-cell activity and abnormal T-cell signalling. The mitogen-activated protein kinase (MAPK) pathway is involved in the maintenance of T-cell tolerance that fails in patients with SLE. Oestrogen is a female sex hormone that binds to nuclear receptors and alters the rate of gene transcription. Oestrogen can also act through the plasma membrane and rapidly stimulate second messengers including calcium flux and kinase activation. In this study, we investigated whether oestrogen influences the activation of MAPK signalling through the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in activated SLE T cells. SLE and control T cells were cultured in serum-free medium without and with oestradiol (10(-7) M) for 18 h. The T cells were activated with phorbol 12 myristate 13-acetate and ionomycin for various time points (0-60 min), and the amount of phosphorylated ERK1/2 was measured by immunoblotting. There were no differences in ERK1/2 phosphorylation between SLE and control T cells at 5 and 15 min after the activation stimulus. However, comparison between the amount of phosphorylated ERK1/2 in SLE T cells from the same patients cultured without and with oestradiol showed a significant oestrogen-dependent suppression (P=0.48) of ERK1/2 in patients with inactive/mild systemic lupus erythematosus disease activity index (SLEDAI) (0-2) compared with patients with moderate (4-6) or active (8-12) SLEDAI scores. These results suggest that the suppression of MAPK through ERK1/2 phosphorylation is sensitive to oestradiol in patients with inactive or mild disease, but the sensitivity is not maintained when disease activity increases. Furthermore, studies are now necessary to understand the mechanisms by which oestrogen influences MAPK activation in SLE T cells.
Lupus 2008 Jun
PMID:Extracellular signal-regulated kinase 1/2 signalling in SLE T cells is influenced by oestrogen and disease activity. 1853 8

Bz-423 is a proapoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen-activated protein kinase cascade follows, leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent on both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevents Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that the selectivity of Bz-423 observed in vivo results from cell-type specific differences in redox balance and signaling by ASK1 and Bcl-2 proteins.
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PMID:Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax. 1871 27


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