Cytokine Production (IL-6 and TNFa) in Whole Blood Cell Cultures of Patients with Systemic Lupus Erythematosus

Swaak, A. J. G.; Brink, H. G. Van Den; Aarden, L. A.

doi:10.3109/03009749609069992

Cited by 38 publications

(25 citation statements)

References 29 publications

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“…This is further confirmed by the finding that monocytes from normal subjects or patients need to be stimulated ex vivo to produce significant amounts of cytokines. [17][18][19] Therefore, serum factors might display an inhibitory activity in the vascular compartment, whereas during the initial inflammatory events in the target tissue, monocyte activation by cellular contact might occur in the absence of such inhibitory factors. In a subsequent phase, due to the increase in vascular permeability at the inflammatory site, these factors might diffuse in the extravascular compartment and interfere with the cross-talk between cells.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Hyka¹,

Dayer²,

Modoux³

et al. 2001

Blood

368

243

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Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), 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-␣ and IL-1␤. 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 highdensity lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-␣ and IL-1␤ 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 antiinflammatory 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. IntroductionTumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) are strongly induced in monocytes by direct contact with stimulated T lymphocytes, both cells involved in immunoinflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis. The importance of TNF-␣ and IL-1 in chronic inflammation has been well established. Based on the premise that T lymphocytes play a pivotal role in the pathogenesis of chronic inflammatory diseases, we demonstrated that direct cell-cell contact with stimulated T lymphocytes is a major stimulus triggering the production of large amounts of TNF-␣ and IL-1␤ in monocytes. [1][2][3] Various stimuli are able to induce T cells to activate monocytes by direct cellular contact: (1) mitogens, for example, a combination of phytohemagglutinin (PHA) and phorbol myristate acetate (PMA), 1,4-6 (2) cross-linking of CD3 by immobilized anti-CD3 monoclonal antibody (mAb) with or without cross-linking of the costimulatory molecule CD28, 7,8 (3) antigen-recognition on antigen-specific T-cell clones, 8 and (4) cytokines. 9 The identity of the ligands on plasma membrane of stimulated T cells that trigger the signaling of monocytemacrophages as well as that of the counter-ligands on monocytes is still elusive. However, in the human system some of the signaling may be attributed to ␤ 2 -integrins, CD69, CD23, CD40-CD40L and lymphocyte activation gene-3 (LAG-3). 1,4,5,10-14 Membrane-associated TNF-␣ and IL-1 do not play a crucial part in this cellular interaction, contrasting with their sign...

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Section: Introductionmentioning

confidence: 99%

Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Hyka¹,

Dayer²,

Modoux³

et al. 2001

Blood

368

243

View full text Add to dashboard Cite

show abstract

“…As examples, ROIs regulate gene transcription and release of TNF-α and IL-10 [35], both of which are elevated in sera [36] and freshly isolated PBLs of SLE patients [37]. Expression of the TCRζ chain is sensitive to oxidative stress [14] and thus increased ROI levels could explain, at least in part, the low expression of the TCRz chain in lupus T cells [38].…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

2004

Trends in Immunology

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T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

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“…In addition, certain studies have demonstrated increased production of these cytokines by peripheral blood mononuclear cell cultures spontaneously or after stimulation, suggesting that cells from these patients may have a generalized increased capacity for the production of pro-inflammatory cytokines. 3,4,7 Not all studies have been consistent, and one study utilizing flow cytometry of stimulated cells demonstrated decreased levels of intracellular TNF␣ in systemic lupus erythematosus (SLE) patients compared to controls. [8][9][10][11] Data from murine SLE models have also been conflicting.…”

mentioning

confidence: 99%

“…This study was based on previous data demonstrating an effect of a TNF␣ ligand polymorphism with SLE, [18][19][20][21][22][23] in vitro data suggesting over-production of TNF␣ by SLE patients, 3,4,7,31,32 and the identification of a putative disease susceptibility locus at 1p32.1, near the TNFR2 locus. 25 Failure to identify an association of this polymorphism with SLE suggests several possibilities.…”

mentioning

confidence: 99%

“…Serum levels of pro-inflammatory cytokines such as IL-1, IL-6, and TNF␣ have been found to correlate with SLE disease activity in most studies, [1][2][3][4][5][6] suggesting that they may represent a driving force behind disease progression or pathology. In addition, certain studies have demonstrated increased production of these cytokines by peripheral blood mononuclear cell cultures spontaneously or after stimulation, suggesting that cells from these patients may have a generalized increased capacity for the production of pro-inflammatory cytokines.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A TNFR2 3′ flanking region polymorphism in systemic lupus erythematosus

Sullivan

Piliero

Goldman³

et al. 2000

Genes Immun

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Cytokine Production (IL-6 and TNFa) in Whole Blood Cell Cultures of Patients with Systemic Lupus Erythematosus

Cited by 38 publications

References 29 publications

Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

A TNFR2 3′ flanking region polymorphism in systemic lupus erythematosus

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