Dataset Information

Quinacrine Suppresses Tumor Necrosis Factor-? and IFN-? in Dermatomyositis and Cutaneous Lupus Erythematosus.

ABSTRACT: Antimalarials are used to treat dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Although hydroxychloroquine (HCQ) is frequently used, addition of quinacrine (QC) has shown additional clinical effects when combined with HCQ. To quantify the effects of HCQ versus QC in suppressing secretion of tumor necrosis factor-? (TNF-?) and IFN-? from the peripheral blood mononuclear cells of DM and CLE patients, lipopolysaccharide-stimulated and control peripheral blood mononuclear cells from DM and CLE patients and control subjects were analyzed for the effect of HCQ and QC on TNF-? and IFN-? production using ELISA testing. Flow cytometry showed the effects of these therapies on intracellular TNF-? in myeloid dendritic cells and monocytes of DM patients and control subjects. QC significantly suppressed TNF-? relative to HCQ from unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). It suppressed IFN-? as significantly as HCQ from cytosine phosphodiester guanine-stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). Flow cytometry showed that QC significantly suppressed intracellular expression of TNF-? from the lipopolysaccharide-stimulated myeloid dendritic cells and monocytes of DM patients (P-values ? 0.0008). In conclusion, QC likely has a different mechanism of action than HCQ, given the broader inhibition of proinflammatory cytokines, including both TNF-? and IFN-?.

SUBMITTER: Alves P

PROVIDER: S-EPMC5645024 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus.

Alves Paul P Bashir Muhammad M MM Wysocka Maria M Zeidi Majid M Feng Rui R Werth Victoria P VP

The journal of investigative dermatology. Symposium proceedings 20171001 2

Antimalarials are used to treat dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Although hydroxychloroquine (HCQ) is frequently used, addition of quinacrine (QC) has shown additional clinical effects when combined with HCQ. To quantify the effects of HCQ versus QC in suppressing secretion of tumor necrosis factor-α (TNF-α) and IFN-α from the peripheral blood mononuclear cells of DM and CLE patients, lipopolysaccharide-stimulated and control peripheral blood mononuclear cells from D ...[more]

PMID: 28941496

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Project description:To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).Tumor necrosis factor ? (TNF?) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNF?(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-?/?/? receptor-knockout (IFNAR(-/-) ), and B cell-deficient (?mt) mice treated with pristane. Flow cytometry was used to examine TNF? production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNF? overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNF? was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNF? production was abolished in pristane-treated TLR-7(-/-) and ?mt mice but was restored in ?mt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNF?(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNF?(-/-) mice.Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNF? driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNF? production mediating glomerulonephritis and hematologic involvement, respectively.

Project description:Systemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study sought to evaluate the changes in plasma concentrations of soluble mediators that precede clinically defined disease flares.Fifty-two different soluble mediators, including cytokines, chemokines, and soluble receptors, were examined using validated multiplex bead-based or enzyme-linked immunosorbent assays in plasma from 28 European American patients with SLE who developed disease flare 6 or 12 weeks after a baseline assessment (preflare), 28 matched SLE patients without impending flare (nonflare), and 28 matched healthy controls. In a subset of 13 SLE patients, mediators within samples obtained preceding disease flare were compared with those within samples from the same individual obtained during a clinically stable period without flare.Compared to SLE patients with clinically stable disease, SLE patients with impending flare had significant alterations (P ? 0.01) in the levels of 27 soluble mediators at baseline; specifically, the levels of proinflammatory mediators, including Th1-, Th2-, and Th17-type cytokines, were significantly higher several weeks before clinical flare. Baseline levels of regulatory cytokines, including interleukin-10 and transforming growth factor ?, were higher in nonflare SLE patients, whereas baseline levels of soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L were significantly higher (P ? 0.002) in preflare SLE patients. The normalized and weighted combined soluble mediator score was significantly higher (P ? 0.0002) in preflare samples from SLE patients compared to samples from the same patients obtained during periods of stable disease.The levels of proinflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while the levels of regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher the pathogenic mechanisms of SLE.

Dataset Information

Quinacrine Suppresses Tumor Necrosis Factor-? and IFN-? in Dermatomyositis and Cutaneous Lupus Erythematosus.

Publications

Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus.

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