Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

Graninger, W; Steiner, Carl-Walter; Graninger, Marianne; Aringer, Martin; Smolen, Josef S

doi:10.1038/sj.cdd.4400724

Cited by 46 publications

(29 citation statements)

References 38 publications

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“…In contrast to ced-9 in C. elegans, mammalian homologues have both antiand proapoptotic genes (inhibitors such as Bcl-2 and promoters such as Bax), and proapoptotic equilibrium of bcl-2 family may appear in lymphocytes from SLE patients (41)(42)(43). Alternatively, the withdrawal of growth factors and cytokines may have a paracrine and/or autocrine role, as shown for lymphocytes (43,44). However, recent reports explored death mechanisms appearing specifically in monocytes and monocytes maturing to macrophages in healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Shoshan

Shapira

Toubi

et al. 2001

The Journal of Immunology

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Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% ± 37 of that of healthy individuals (p < 0.002) and 69% ± 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

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Section: Discussionmentioning

confidence: 99%

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Shoshan

Shapira

Toubi

et al. 2001

The Journal of Immunology

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“…The defects in thymopoeisis in mice lacking IL-7 or IL-7Ra can be substantially rescued by over-expression of Bcl2 [12,13], or by compound deficiency with pro-apoptotic molecules such as Bax [14] or Bim [15]. In vitro, it has long been recognized that IL-7 stimulation of mutant T-cell lines or primary T cells up-regulates Bcl2 [12,13,[16][17][18], as well as Mcl1 [19]. Conversely, there have been other reports suggesting that Bcl2 expression is reduced in the absence of IL-7 signalling [3,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

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The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Ra, we show that T-cell longevity in the absence of survival cues is not a cellintrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Ra expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is nonlimiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.Key words: Fitness . Homeostasis . IL-7 . T cells Supporting Information available onlineIntroduction A commonly evoked concept in studies of lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state, or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness [1]. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of 9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.Ã These authors contributed equally to this work. 3656The mechanisms by which IL-7 maintains T-cell survival, and therefore regulate cellular fitness, have been the subject of numerous studies. Many of these have focused on the transc...

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“…Several members of the Bcl-2 family have previously been reported to be aberrantly expressed in lupus B cells (26)(27)(28). Levels of the antiapoptotic molecules Bcl-2 and Bcl-xl and the proapoptotic molecules Bim and Bax were assayed in unmanipulated or stimulated splenic B cells from B6.Sle1 z and B6.Sle1 z .Sle3 z congenics.…”

Section: Figurementioning

confidence: 99%

Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus

et al. 2007

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Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/ mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-κB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.

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Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

Cited by 46 publications

References 38 publications

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus

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