IL-4 and IL-13, But Not IL-10, Protect Human Synoviocytes from Apoptosis

Relić, Biserka; Guicheux, Jérôme; Mézin, Françoise; Lubberts, Erik; Togninalli, D.; García, Irene; Berg, Wim B. van den; Guerne, Pierre‐André

doi:10.4049/jimmunol.166.4.2775

Cited by 75 publications

(67 citation statements)

References 32 publications

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“…The antiapoptotic role of IL4Ra was elucidated in many cell types including B cells, T cells, masT cells, and myeloid cells but, until now, not in MDSCs. Interestingly, IL-13 pretreatment has been shown to protect human synoviocytes from nitric oxide-induced apoptosis by inducing IRS phosphorylation and PKC activation (45). Although we have not yet confirmed this pathway in MDSCs, it is possible that IRS activation by IL4Ra is necessary for protecting MDSCs from the autocrinally produced NO and that the aptamermediated blockade of this pathway prevents this protective mechanism.…”

Section: Discussionmentioning

confidence: 68%

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

et al. 2012

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In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloidderived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-a (IL4Ra or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Ra aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumorinfiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Ra signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Ra signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Res; 72(6); 1373-83. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 68%

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

et al. 2012

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“…For instance, IL-4, but not IL-10, has antiapoptotic effects on synoviocytes. 53 The differential mechanisms of the regulation of T-cell synthesis of OPG by IL-4 and IL-10 remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Chakravarti

Marceau

Flamand

et al. 2008

Laboratory Investigation

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Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG regulates bone remodeling and the immune response. The primary objective was to decipher, among human peripheral blood mononuclear leukocytes (PBML) that produce OPG, the subset(s) responsible for this synthesis and its regulation. To this end, normal human PBML and CD4-, 8-, 19-, 14-enriched subpopulations were studied in vitro for OPG synthesis. PBML were subjected to adherence and immunomagnetic separation, and OPG expression was analyzed by PCR, northern and western blotting, and ELISA. The antiapoptotic effects of OPG were studied on TRAIL-stimulated RPMI 8226 myeloma cells. OPG was time-dependently produced by primary CD4 þ T lymphocytes exclusively. OPG secretion was upregulated by anti-CD3 antibody stimulation or incubation with interleukin (IL)-4, IL-1b, TNF-a, GM-CSF, and vitamin D 3 . In contrast, IL-10 inhibited the basal and IL-4-induced production of OPG by T cells. Conditioned media from activated T lymphocytes decreased TRAIL-induced apoptosis of RPMI 8226 cells. This effect was reversed by addition of RANKL to the T-cell conditioned media. As human immunodeficiency virus-1 (HIV-1) targets CD4 þ T cells, we evaluated the effects of recombinant HIV-1 gp120 proteins on OPG synthesis. The gp120 from three different HIV-1 strains significantly reduced the basal output of OPG from T cells. Furthermore, all four protease inhibitors (PIs) used in highly active antiretroviral therapy decreased OPG synthesis by human blood T cells, nelfinavir being the most efficient PI. The simultaneous presence of an HIV-1 gp120 and a PI abrogated the basal output of OPG. In conclusion, these results highlight a new role for T lymphocytes involved in pathologies. Activated CD4 þ T cells could, through OPG release, have a paracrine effect on adjacent cells and contribute to reduce the local process of bone remodeling and cellular apoptosis.

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“…Cytokines, including IL-4 and IL-13, have been shown to have antiapoptotic effects in human synoviocytes, possibly via effects on caspases (34). To date, however, these cytokines have not been shown to influence p53 expression.…”

Section: Discussionmentioning

confidence: 99%

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

Leech

Lacey

Xue

et al. 2003

Arthritis & Rheumatism

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Objective. To study the capacity of macrophage migration inhibitory factor (MIF) to regulate proliferation, apoptosis, and p53 in an animal model of rheumatoid arthritis (RA) and in fibroblast-like synoviocytes (FLS) from humans with RA.Methods. Antigen-induced arthritis (AIA) was induced in MIF -/-mice and littermate controls. FLS were obtained from patients with RA. Western blotting and immunohistochemistry were used to measure p53 in cells and tissues. Apoptosis was detected in cells by flow cytometry using TUNEL and annexin V/propidium iodide labeling. Apoptosis in tissue was detected using TUNEL. Proliferation was assessed in cultured cells and tissue by 3 H-thymidine incorporation and Ki-67 immunostaining, respectively.Results. MIF inhibited p53 expression in human RA FLS. Levels of p53 were correspondingly increased in MIF -/-mouse tissues and cells. Spontaneous and sodium nitroprusside-induced apoptosis were significantly increased in MIF -/-cells. In vitro exposure of FLS to MIF reduced apoptosis and significantly induced FLS proliferation. Synoviocyte proliferation in MIF -/-mice was correspondingly reduced. A decrease in the severity of AIA in MIF -/-mice was associated with an increase in p53 and apoptosis in synovium. Evidence of in situ proliferation was scant in this model, and no difference in in situ proliferation was detectable in MIF -/-mice compared with wild-type mice.Conclusion. These results indicate a role for MIF in the regulation of p53 expression and p53-mediated events in the inflamed synovium and support the hypothesis that MIF is of critical importance in the pathogenesis of RA.

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IL-4 and IL-13, But Not IL-10, Protect Human Synoviocytes from Apoptosis

Cited by 75 publications

References 32 publications

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

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