Genome-wide Profiling of Interleukin-4 and STAT6 Transcription Factor Regulation of Human Th2 Cell Programming

Biomathematics Research Group, Department of Mathematics, University of Turku, FI-20014 Turku, Finland.
Immunity (Impact Factor: 21.56). 06/2010; 32(6):852-62. DOI: 10.1016/j.immuni.2010.06.011
Source: PubMed


Dissecting the molecular mechanisms by which T helper (Th) cells differentiate to effector Th2 cells is important for understanding the pathogenesis of immune-mediated diseases, such as asthma and allergy. Because the STAT6 transcription factor is an upstream mediator required for interleukin-4 (IL-4)-induced Th2 cell differentiation, its targets include genes important for this process. Using primary human CD4(+) T cells, and by blocking STAT6 with RNAi, we identified a number of direct and indirect targets of STAT6 with ChIP sequencing. The integration of these data sets with detailed kinetics of IL-4-driven transcriptional changes showed that STAT6 was predominantly needed for the activation of transcription leading to the Th2 cell phenotype. This integrated genome-wide data on IL-4- and STAT6-mediated transcription provide a unique resource for studies on Th cell differentiation and, in particular, for designing interventions of human Th2 cell responses.

Download full-text


Available from: Sunil kumar Raghav,
  • Source
    • "Further studies are needed to detail STAT6 ability to affect chemokine transcriptional control in human chondrocytes. Indeed, in most of the cellular models considered to date, the IL-4-dependent regulation of inflammatory gene expression has been mainly attributed to the STAT6 transcription factor [20], [49], [50]. The promoter region of the human chemokine genes harbors putative binding sites for a number of well-described transcription factors (e.g: C/EBP, NF-κB, AP-1, IRF) which vary in their quantitative and qualitative contribution among specific sets of chemokine genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In osteoarthritis (OA), an inflammatory environment is responsible for the imbalance between the anabolic and catabolic activity of chondrocytes and, thus, for articular cartilage derangement. This study was aimed at providing further insight into the impairment of the anabolic cytokine IL-4 and its receptors in human OA cartilage, as well as the potential ability of IL-4 to antagonize the catabolic phenotype induced by IL-1β. The in vivo expression of IL-4 and IL-4 receptor subunits (IL-4R, IL-2Rγ, IL-13Rα1) was investigated on full thickness OA or normal knee cartilage. IL-4 expression was found to be significantly lower in OA, both in terms of the percentage of positive cells and the amount of signal per cell. IL-4 receptor type I and II were mostly expressed in mid-deep cartilage layers. No significant difference for each IL-4 receptor subunit was noted. IL-4 anti-inflammatory and anti-catabolic activity was assessed in vitro in the presence of IL-1β and/or IL-4 for 24 hours using differentiated high density primary OA chondrocyte also exhibiting the three IL-4 R subunits found in vivo. Chemokines, extracellular matrix degrading enzymes and their inhibitors were evaluated at mRNA (real time PCR) and protein (ELISA or western blot) levels. IL-4 did not affect IL-1β-induced mRNA expression of GRO-α/CXCL1, IL-8/CXCL8, ADAMTS-5, TIMP-1 or TIMP-3. Conversely, IL-4 significantly inhibited RANTES/CCL5, MIP-1α/CCL3, MIP-1β/CCL4, MMP-13 and ADAMTS-4. These results were confirmed at protein level for RANTES/CCL5 and MMP-13. Our results indicate for the first time that OA cartilage has a significantly lower expression of IL-4. Furthermore, we found differences in the spectrum of biological effects of IL-4. The findings that IL-4 has the ability to hamper the IL-1β-induced release of both MMP-13 and CCL5/RANTES, both markers of OA chondrocytes, strongly indicates IL-4 as a pivotal anabolic cytokine in cartilage whose impairment impacts on OA pathogenesis.
    PLoS ONE 05/2014; 9(5):e96925. DOI:10.1371/journal.pone.0096925 · 3.23 Impact Factor
  • Source
    • "Various permissive epigenetic marks were coincided with specific STAT6-bound regions and IL-4, Gata3, IL-24, phospholipase C δ 1 and homeodomain interacting protein kinase 2 were included in the corresponding genes (58). In an additional study, human Th2 cells were used and compared with the STAT6 binding to genes between cells where the expression of STAT6 was knocked down by RNA interference and cells with normal STAT6 expression (59). In the present study, a kinetic analysis was performed and the identity of STAT6-dependent genes during the Th2 polarization process was determined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although interleukin-9 (IL-9) exhibits pleiotropic functions in the immune system, it remains a well-known cytokine in hematological malignancies. Previous cell culture and animal model studies have revealed that the Janus kinase-signal transducer and activator of transcription signaling pathway, which may be activated by a number of cytokines including IL-9, is critical in hematological malignancies. The current review summarizes the characterization of the biological activities of IL-9, highlights the clearly defined roles of the cytokine, and outlines questions with regard to the functions of IL-9 that require further exploration and their downstream signaling proteins, signal transducers and activators of transcription.
    Oncology letters 03/2014; 7(3):602-610. DOI:10.3892/ol.2013.1761 · 1.55 Impact Factor
  • Source
    • "On the other hand, in Stat6-/- cells the suppressive effects of IL-4 remained largely unchanged, pointing to an IL-4 induced signaling branch that operates independently of Stat6. Similar interdigitation of IL-4 and Stat6 signaling has been observed in the context of Th2 differentiation [106,107]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control. As transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H+ ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4. The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling.
    BMC Genomics 12/2013; 14(1):853. DOI:10.1186/1471-2164-14-853 · 3.99 Impact Factor
Show more