IL-1β and TGF-β Act Antagonistically in Induction and Differentially in Propagation of Human Proinflammatory Precursor CD4+ T Cells

Hebel, Katrin; Rudolph, Marion; Kosak, Bernhard; Chang, Hyun‐Dong; Butzmann, Jana; Brunner‐Weinzierl, Monika C.

doi:10.4049/jimmunol.1003998

Cited by 64 publications

(58 citation statements)

References 55 publications

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“…Thus, the combined effect of the miRs belonging to factors 2 and 3 could be increased expression in octogenarians and lower expression in centenarians. TGF-b is one of the most potent endogenous modulators of inflammation, with a well-documented anti-inflammatory effect (Breit et al, 2011;Hebel et al, 2011). Moreover, the inactivation of different components of the TGF-b signaling pathway caused CVD-related vascular dysfunction in both mice and humans (Pardali and Ten Dijke, 2012;Aihara et al, 2010).…”

Section: Discussionmentioning

confidence: 94%

Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging

Olivieri

Spazzafumo

Santini

et al. 2012

Mechanisms of Ageing and Development

215

151

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Section: Discussionmentioning

confidence: 94%

Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging

Olivieri

Spazzafumo

Santini

et al. 2012

Mechanisms of Ageing and Development

215

151

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“…IL-1β has just recently been shown to induce a general proinflammatory T-cell phenotype on its own and in this context to be able to promote IL-17A-independent of RORγt [35]. Blocking IL-1β-mediated signaling has been discussed as a new treatment option in central nervous system diseases and in particular in MS [36].…”

Section: Discussionmentioning

confidence: 99%

Boswellic acids reduce Th17 differentiation via blockade of IL‐1β‐mediated IRAK1 signaling

et al. 2014

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Interferon-gamma producing CD4+ T (Th1) cells and IL-17-producing CD4 + T (Th17) cells are involved in the pathogenesis of several autoimmune diseases including multiple sclerosis. Therefore, the development of treatment strategies controlling the generation and expansion of these effector cells is of high interest. Frankincense, the resin from trees of the genus Boswellia, and particularly its prominent bioactive compound acetyl-11-keto-β-boswellic acid (AKBA), have potent anti-inflammatory properties. Here, we demonstrate that AKBA is able to reduce the differentiation of human CD4 + T cells to Th17 cells, while slightly increasing Th2-and Treg-cell differentiation. Furthermore, AKBA reduces the IL-1β-triggered IL-17A release of memory Th17 cells. AKBA may affect IL-1β signaling by preventing IL-1 receptor-associated kinase 1 phosphorylation and subsequently decreasing STAT3 phosphorylation at Ser727, which is required for Th17-cell differentiation. The effects of AKBA on Th17 differentiation and IL-17A release make the compound a good candidate for potential treatment of Th17-driven diseases.Keywords: AKBA r boswellic acids r Th17 cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction IFN-γ producing CD4 + T (Th1) cells and IL-17-producing CD4 + T (Th17) cells mediate tissue damage and inflammation in several animal models of autoimmune diseases such as EAE, collageninduced arthritis and experimental colitis [1][2][3]. In addition, involvement of these cells in human autoimmune diseases including multiple sclerosis (MS) [4][5][6], rheumatoid arthritis [7], and Crohn's disease [8,9] is supported by the accumulation and upregulation of Th1-and Th17 signature cytokines Correspondence: Dr. Mireia Sospedra e-mail: Mireia.SospedraRamos@usz.ch in the target tissues. Treatment strategies controlling the generation and expansion of these effector cells could be very useful therapeutically. Th17 cells are generated under different polarizing conditions than Th1 cells and, although polarization of human Th17 cells has been extensively investigated, the differentiation requirements are still incompletely defined. It has been reported that the coordinated activation of Smad 3 and STAT3 induce the transcription factor RORγt necessary for Th17-cell differentiation [10]. Full activation of STAT3 requires phosphorylation of Tyrosine 705 (Y705) * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1200-1212 Clinical immunology 1201and Serine 727 (S727) sites and these phosphorylations are controlled by different kinases. Janus Kinase 2 (JAK2) controls phosphorylation of Y705 [11], while phosphorylation of S727 is controlled by IL-1 receptor-associated kinase 1 (IRAK1) [12]. IL-6 and IL-1β are two cytokines reported to be essential for human Th17-cell differentiation [13,14]. Th17-cell activation requires full activation of STAT3 by phosphorylation, and IL-6 and...

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“…To determine whether Th cells from infants spontaneously differentiate into Th2 cells, leukocytes were isolated from adenoids and stimulated for 16 h with either anti-CD3-and anti-CD28-coated microbeads (33) or PMA and ionomycin. Subsequently, the expression of IL-4, the master cytokine for Th2 development, and its isoform was analyzed by flow cytometry (Fig.…”

Section: Infant Cd4 + T Cells Express the Il-4(8d4-8) Isoform At Highmentioning

confidence: 99%

CD4+ T Cells from Human Neonates and Infants Are Poised Spontaneously To Run a Nonclassical IL-4 Program

Hebel

Weinert

Kuropka

et al. 2014

The Journal of Immunology

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Senescence or biological aging impacts a vast variety of molecular and cellular processes. To date, it is unknown whether CD4+ Th cells display an age-dependent bias for development into specific subpopulations. In this study, we show the appearance of a distinct CD4+ T cell subset expressing IL-4 at an early stage of development in infant adenoids and cord blood that is lost during aging. We identified by flow cytometric, fluorescent microscopic, immunoblot, and mass spectrometric analysis a population of CD4+ T cells that expressed an unglycosylated isoform of IL-4. This T cell subpopulation was found in neonatal but not in adult CD4+ T cells. Furthermore, we show that the mRNA of the Th2 master transcription factor GATA3 is preferentially expressed in neonatal CD4+ T cells. The Th2 phenotype of the IL-4+CD4+ T cells could be reinforced in the presence of TGF-β. Although the IL-4+CD4+ T cells most likely originate from CD31+CD4+ T recent thymic emigrants, CD31 was downregulated prior to secretion of IL-4. Notably, the secretion of IL-4 requires a so far unidentified trigger in neonatal T cells. This emphasizes that cytokine expression and secretion are differentially regulated processes. Our data support the hypothesis of an endogenously poised cytokine profile in neonates and suggest a link between cytokine production and the developmental stage of an organism. The determination of the IL-4 isoform–expressing cells in humans might allow the identification of Th2 precursor cells, which could provide novel intervention strategies directed against Th2-driven immunopathologies such as allergies.

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IL-1β and TGF-β Act Antagonistically in Induction and Differentially in Propagation of Human Proinflammatory Precursor CD4+ T Cells

Cited by 64 publications

References 55 publications

Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging

Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging

Boswellic acids reduce Th17 differentiation via blockade of IL‐1β‐mediated IRAK1 signaling

CD4+ T Cells from Human Neonates and Infants Are Poised Spontaneously To Run a Nonclassical IL-4 Program

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