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)

Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN-alpha diminished the ability of IL-10 to suppress TNF-alpha production. IFN-alpha conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-gamma-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN-gamma-inducible protein-10 (CXCL10), and monokine induced by IFN-gamma (CXCL9). IFN-alpha priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma expression in IFN-alpha-primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.
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PMID:IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. 1512 40

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.
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PMID:Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia. 1616 74

Synthetic oligodeoxynucleotides (ODNs) expressing immunosuppressive TTAGGG motifs downregulate the production of proinflammatory and Th1 cytokines. The ability of these "suppressive ODNs" to slow or prevent the development of diseases characterized by over-exuberant immune stimulation was examined. Suppressive ODNs significantly reduced disease severity in murine models of arthritis, lupus, and LPS-induced toxic shock. These beneficial effects were accompanied by a significant reduction in serum autoantibody and cytokine levels. Underlying these protective effects was the ability of suppressive ODNs to bind to and prevent the phosphorylation of STAT1 and STAT4, thereby blocking the signaling cascade central to the initiation and/or perpetuation of these disease states. These findings suggest that suppressive ODNs might find use in the treatment of acute and chronic diseases characterized by excessive immune stimulation.
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PMID:Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs. 1639 28

Interferons (IFNs), type I (alpha/beta) and type II (gamma), comprise a family of multifunctional cytokines with antiviral, antiproliferative and immunomodulating properties. Both type I and type II IFNs have been heavily implicated in the pathogenesis of systemic lupus erythematosus (SLE). The biological effects of IFNs are mediated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in which both IFN-alpha/beta and IFN-gamma activate the transcription factor STAT1. However, little is known about the pathogenic significance of STAT1 in SLE. At this point, we examined the expression and activation of STAT1 in the kidney of MRL/lpr mice with lupus nephritis (LN) by immunohistochemistry, Western botting and real time quantitative RT-PCR. Increased levels of total STAT1 protein and its activated/phosphorylated form were detected in kidney samples from MRL/lpr mice with LN as compared to those from control mice. Phosphorylated STAT1 was predominantly detected in glomeruli cells. Gene expression of the STAT induced feedback inhibitors suppressor of cytokine signalling-1 (SOCS-1) and SOCS-3 was also enhanced in MRL/lpr mice. In MRL/lpr mesangial cells, both IFN-alpha and IFN-gamma rapidly induced the phosphorylation of STAT in vitro. Our results demonstrate that expression and activation of STAT1 are significantly increased in murine lupus nephritis, and indicate that STAT1 signalling pathway may play an important role in the pathogenesis of kidney inflammation.
Lupus 2007
PMID:Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. 1740 66

A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21-1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P=0.0027, OR (95 percent CI)=1.33 (1.10-1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
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PMID:Association of STAT4 with rheumatoid arthritis in the Korean population. 1793 59

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

Immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors modulate the amplitude and nature of macrophage responses to Toll-like receptor and cytokine receptor stimulation. However, the molecular mechanisms enabling this receptor crosstalk are not known. Here we investigated the function of the calcium-dependent kinases CaMK and Pyk2 'downstream' of ITAM-associated receptors in the regulation of cytokine-induced activation of Jak kinases and STAT transcription factors. CaMK and Pyk2 relayed signals from integrins and the ITAM-containing adaptor DAP12 to augment interleukin 10- and interferon-alpha-induced Jak activation and STAT1-dependent gene expression. CaMK inhibition suppressed STAT1-mediated interferon-alpha signaling in a mouse model of systemic lupus erythematosus. Our results associate Pyk2 and Jak kinases with the linkage of signals emanating from cytokine and heterologous ITAM-dependent receptors.
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PMID:'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. 1808 94

A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.
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PMID:IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice. 1834 Mar 81

Treatment of (NZB x NZW)F(1) (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.
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PMID:Modulation of p38 MAPK activity in regulatory T cells after tolerance with anti-DNA Ig peptide in (NZB x NZW)F1 lupus mice. 1949 64

Cytokines are known to play an important role in the pathogenesis of lupus nephritis (LN) and the Jak/STAT (Janus kinase-signal transducer and activator of transcription factor) pathway is important in mediating signal transduction of cytokines. This study examined the pathogenic role of Jak/STAT signaling in LN. MRL/lpr mice were either treated with a selective Jak2 inhibitor tyrphostin AG490 or with vehicle alone from 12 weeks of age until being sacrificed at week 20. AG490 significantly inhibited the phosphorylation of Jak2 and STAT1 (p < 0.05). Compared with the vehicle-treated mice, AG490 treatment significantly reduced proteinuria, improved renal function and suppressed histological lesions of the kidneys and salivary glands (p < 0.05). AG490 treatment significantly inhibited the renal expression of monocyte chemotactic protein (MCP)-1, interferon (IFN)-gamma and class II MHC, which was accompanied by reduced renal infiltration of T cells and macrophages (p < 0.05). In addition, AG490 treatment resulted in a decrease in serum anti-double-stranded DNA (anti-dsDNA) antibody and attenuated the deposition of IgG and C3 in the kidneys (p < 0.05). This study demonstrated that Jak/STAT pathway is implicated in the progression of renal inflammation in MRL/lpr mice and targeting this pathway may provide a potential therapeutic approach for LN.
Lupus 2010 Sep
PMID:Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice. 2050 25


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