Interleukin-4 (IL-4) receptor expression on human T cells is affected by different intracellular signaling pathways and by IL-4 at transcriptional and posttranscriptional level

Dokter, Wha; Borger, Pieter; Hendriks, Dw; Horst, I van der; Halie, MR; Vellenga, Edo

doi:10.1182/blood.v80.11.2721.bloodjournal80112721

Cited by 6 publications

(11 citation statements)

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“…3a). Dokter et al have reported a similar effect of IL-4 on IL-4Ra mRNA expression in T cells [31]. This upregulation in receptor may have two effects-render the cells more responsive to IL-4 if expressed on the cell surface or less responsive if the receptor is secreted and sequesters IL-4.…”

Section: Discussionmentioning

confidence: 90%

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Anti-inflammatory effects of interleukin-4 on intervertebral disc cells

et al. 2020

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Section: Discussionmentioning

confidence: 90%

“…IL-4 has been shown to upregulate gene expression of IL-4Ra [31], CCL22 [32], and IL-6 [33]. Several studies also showed that IL-4 treatment can reduce IL-6, IL-8, IL-12 mRNA, and protein levels in cells stimulated with inflammatory cytokines or proteins [34−38].…”

Section: Il-4 Treatment Affects the Regulation Of Downstream Genesmentioning

confidence: 99%

Anti-inflammatory effects of interleukin-4 on intervertebral disc cells

et al. 2020

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“…In particular, many other cell types, including those we observe in the inflamed state (Fig. 2 ), possess the IL-4Rα [ 45 – 49 ] and are therefore potential targets of receptor blockade. Future experiments will be necessary to determine the roles of other cell types in promoting Aβ clearance.…”

Section: Discussionmentioning

confidence: 99%

Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation

Cherry

Olschowka

O’Banion

2015

J Neuroinflammation

118

102

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BackgroundNeuroinflammation has long been considered a driver of Alzheimer’s disease progression. However, experiments developed to explore the interaction between neuroinflammation and Alzheimer’s disease (AD) pathology showed a surprising reduction in amyloid beta (Aβ) plaque deposition. We sought to understand this unexpected outcome by examining microglia phenotypes during chronic neuroinflammation.MethodsUsing an adeno-associated virus vector carrying hIL-1β cDNA, inflammation was induced in one hippocampus of 8-month-old amyloid precursor protein (APP)/PS1 mice for 4 weeks, while the other hemisphere received control injections. Bone marrow chimeras and staining analysis were used to identify the origins and types of immune cells present during sustained inflammation. Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS) immunoreactivity were used as markers of alternatively activated and classically activated cells, respectively, and changes in cellular uptake of Aβ by Arg1+ or iNOS+ microglia was demonstrated by confocal microscopy. To determine if an anti-inflammatory phenotype was present during neuroinflammation, RNA was extracted on flow-sorted microglia and rt-PCR was performed. Interleukin-4 injection was used to induce alternatively activated cells, whereas a minipump and intrahippocampal cannula was used to deliver an interleukin (IL)-4Rα antibody to block the induction of Arg1+ cells in the setting of sustained IL-1β expression.ResultsWe observed a robust upregulation of centrally derived Arg1+ microglia present only in the inflamed hemisphere. Furthermore, in the inflamed hemisphere, greater numbers of Arg1+ microglia contained Aβ when compared to iNOS+ microglia. RNA isolated from flow-sorted microglia from the inflamed hemisphere demonstrated elevation of mRNA species consistent with alternative activation as well as neuroprotective genes such as BDNF and IGF1. To explore if Arg1+ microglia mediated plaque reduction, we induced Arg1+ microglia with IL-4 and observed significant plaque clearance. Moreover, when we reduced Arg1+ microglia induction in the context of neuroinflammation using an anti-IL-4Rα antibody delivered via intrahippocampal cannula, we observed a clear correlation between numbers of Arg1+ microglia and plaque reduction.ConclusionsTogether, these findings suggest that Arg1+ microglia are involved in Aβ plaque reduction during sustained, IL-1β-dependent neuroinflammation, opening up possible new avenues for immunomodulatory therapy of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0411-8) contains supplementary material, which is available to authorized users.

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“…IL-4Ra chain expression is regulated by different signalling pathways, including those activated by TCR and IL-4. 34 Upon activation, naive CD4 + T cells up-regulate IL-4Ra chain expression. Our data show that under Th2 polarizing conditions IL-4Ra chain is readily up-regulated and kept at high level during the stimulation period.…”

Section: Discussionmentioning

confidence: 99%

“…IL-4Ra chain expression is regulated by different signalling pathways, including those activated by TCR and IL-4 itself, that lead to its up-regulation during Th2 cell differentiation. 34 IL-4Ra chain expression was examined by Western blot in CD4 + T cells stimulated under Th2 polarizing conditions for 1-5 days. Results show that IL-4Ra chain expression is low in naive CD4 + T cells and increases after stimulation.…”

Section: Ctla-4 Engagement Inhibits Il-4ra Chain Expressionmentioning

confidence: 99%

Cytotoxic T‐lymphocyte antigen‐4 inhibits GATA‐3 but not T‐bet mRNA expression during T helper cell differentiation

et al. 2006

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SummaryNaive CD4 + T-cell differentiation to T helper 1 (Th1) and Th2 cells is dependent on T-bet and GATA-3 factors, respectively. T-bet and GATA-3, indeed, through chromatin remodelling allow transcriptional activation of Ifnc and Th2 cytokine (Il4, Il5, Il13) genes, respectively. We investigated the effects of the negative costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) on GATA-3 and T-bet mRNA expression and Th cell differentiation in mouse naive CD4 + T cells. Our results show that CTLA-4 inhibits GATA-3 mRNA expression and Th2 cell differentiation. At variance, CTLA-4 does not affect T-bet mRNA expression and Th1 cell differentiation. GATA-3 mRNA expression is inhibited when CD4 + cells are stimulated under both neutral (i.e. absence of cytokines) and Th2-polarizing (i.e. presence of interleukin (IL)-4) conditions, the effect being larger under the latter condition. Hence CTLA-4 might affect the IL-4/signal transducer and activator of transcription-6 (STAT6) pathway leading to GATA-3 mRNA up-regulation. We found, indeed, that CTLA-4 engagement inhibits STAT6 activation leaving unaffected the STAT6 protein level. Moreover, CTLA-4 engagement drastically inhibits IL-4Ra mRNA and protein up-regulation under Th2-polarizing conditions. Thus, CTLA-4 exerts a tight control on Th2 cell differentiation by negatively regulating both the CD3/CD28 and the IL-4/STAT6 pathways.

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Interleukin-4 (IL-4) receptor expression on human T cells is affected by different intracellular signaling pathways and by IL-4 at transcriptional and posttranscriptional level

Cited by 6 publications

References 0 publications

Anti-inflammatory effects of interleukin-4 on intervertebral disc cells

Anti-inflammatory effects of interleukin-4 on intervertebral disc cells

Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation

Cytotoxic T‐lymphocyte antigen‐4 inhibits GATA‐3 but not T‐bet mRNA expression during T helper cell differentiation

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