The role of IL&amp;hyphen;11 in hematopoiesis as revealed by a targeted mutation of its receptor

Nandurkar, Harshal; Robb, Lorraine; Begley, C. Glenn

doi:10.1002/stem.5530160708

Cited by 30 publications

(19 citation statements)

References 74 publications

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“…Further downstream targets of bFGF are transcription factors involved in proliferation such as c-FOS, c-JUN, MYC, and ETS2 (Greber et al, 2007a). Also IL-11 was up-regulated which is traditionally known to be involved in proliferation in the hematopoetic system (Nandurkar et al, 1998). Like the bFGF pathway, the inhibition of TGFβ which acts via SMAD2/3 signaling induces differentiation in hESCs (Greber et al, 2008), PI3K/AKT signaling is repressed upon embryoid body formation (Armstrong et al, 2006) and it was discovered that IGFII initiates this signaling pathway by binding to IGFR1 (Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

et al. 2013

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Pluripotency in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is regulated by three transcription factors—OCT3/4, SOX2, and NANOG. To fully exploit the therapeutic potential of these cells it is essential to have a good mechanistic understanding of the maintenance of self-renewal and pluripotency. In this study, we demonstrate a powerful systems biology approach in which we first expand literature-based network encompassing the core regulators of pluripotency by assessing the behavior of genes targeted by perturbation experiments. We focused our attention on highly regulated genes encoding cell surface and secreted proteins as these can be more easily manipulated by the use of inhibitors or recombinant proteins. Qualitative modeling based on combining boolean networks and in silico perturbation experiments were employed to identify novel pluripotency-regulating genes. We validated Interleukin-11 (IL-11) and demonstrate that this cytokine is a novel pluripotency-associated factor capable of supporting self-renewal in the absence of exogenously added bFGF in culture. To date, the various protocols for hESCs maintenance require supplementation with bFGF to activate the Activin/Nodal branch of the TGFβ signaling pathway. Additional evidence supporting our findings is that IL-11 belongs to the same protein family as LIF, which is known to be necessary for maintaining pluripotency in mouse but not in human ESCs. These cytokines operate through the same gp130 receptor which interacts with Janus kinases. Our finding might explain why mESCs are in a more naïve cell state compared to hESCs and how to convert primed hESCs back to the naïve state. Taken together, our integrative modeling approach has identified novel genes as putative candidates to be incorporated into the expansion of the current gene regulatory network responsible for inducing and maintaining pluripotency.

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Section: Discussionmentioning

confidence: 99%

Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

et al. 2013

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“…SCF, IL-3, G-CSF, GM-CSF, M-CSF, Flt3-L, IL-6, and IL-11 promote myelopoiesis directly and indirectly (43, 66 -68), whereas IFN-␥, IL-1, and TNF-␣ work indirectly (43). Homozygous disruption of the G-CSF gene causes a partial reduction of the number of granulocyte-macrophage progenitors and circulating neutrophils, but no defects in myelopoiesis are evident after disruption of the genes encoding the other factors, indicating a high degree of redundancy (43,66,69). In keeping with this redundancy, we found that deletion of IFN-␥ alone or deletion of the combination of GM-CSF and IL-3 failed to eliminate the myelopoietic response to IL-7.…”

Section: Discussionmentioning

confidence: 99%

IL-7 Induces Myelopoiesis and Erythropoiesis

Aiello

Keller

Klarmann

et al. 2007

The Journal of Immunology

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IL-7 administration to mice was previously reported to increase the mobilization of progenitor cells from marrow to peripheral sites. We now report that IL-7 increases the number of mature myeloid and monocytic cells in spleen and peripheral blood. This effect required T cells, and we show that IL-7 treatment in vivo induced GM-CSF and IL-3 production by T cells with memory phenotype. However, additional myelopoietic cytokines were shown to be involved because mice deficient in both GM-CSF and IL-3 also responded to IL-7 with increased myelopoiesis. Candidate cytokines included IFN-γ and Flt3 ligand, which were also produced in response to IL-7. Because IFN-γ-deficient mice also increased myelopoiesis, it was suggested that IL-7 induced production of redundant myelopoietic cytokines. In support of this hypothesis, we found that the supernatant from IL-7-treated, purified T cells contained myelopoietic activity that required a combination of Abs against GM-CSF, IL-3, and anti-Flt3 ligand to achieve maximum neutralization. IL-7 administration increased the number of splenic erythroid cells in either normal, Rag1 or GM-CSF-IL-3-deficient mice, suggesting that IL-7 might directly act on erythroid progenitors. In support of this theory, we detected a percentage of TER-119+ erythroid cells that expressed the IL-7Rα-chain and common γ-chain. Bone marrow cells expressing IL-7R and B220 generated erythroid colonies in vitro in response to IL-7, erythropoietin, and stem cell factor. This study demonstrates that IL-7 can promote nonlymphoid hemopoiesis and production of cytokines active in the host defense system in vivo, supporting its possible clinical utility.

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“…In mammals, IL-11 is involved in the regulation of the hematopoiesis as it stimulates the proliferation and differentiation of primitive stem cells, as well as multipotent and committed progenitor cells [88]. As the teleostean kidney is believed to be the site for hematopoietic differentiation, including erythropoiesis, granulopoiesis, and lymphopoiesis, a similar importance of fish IL-11 in hematopoiesis could be expected.…”

Section: Resultsmentioning

confidence: 99%

Characterisation and expression analysis of the Atlantic halibut (Hippoglossus hippoglossus L.) cytokines: IL-1β, IL-6, IL-11, IL-12β and IFNγ

et al. 2011

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Genes encoding the five Atlantic halibut (Hippoglossus hippoglossus L.) cytokines; interleukin (IL)-1β, IL-6, IL-11b, IL-12βc, and interferon (IFN) γ, were cloned and characterised at a molecular level. The genomic organisation of the halibut cytokine genes was similar to that seen in mammals and/or other fish species. Several mRNA instability motifs were found within the 3′-untranslated region (UTR) of all cytokine cDNA sequences. The putative cytokine protein sequences showed a low sequence identity with the corresponding homologues in mammals, avian and other fish species. Nevertheless, important structural features were presumably conserved such as the presence, or absence in the case of IL-1β, of a signal peptide, secondary structure and family signature motifs. The relative expression pattern of the cytokine genes was analyzed in several halibut organs, revealing a constitutive expression in both lymphoid and non-lymphoid organs. Interestingly, the gills showed a relatively high expression of IL-1β, IL-12βc and IFNγ. The real time RT-PCR data also showed that the mRNA level of IL-1β, IL-6, IL-12βc and IFNγ was high in the thymus, while IL-11b was relatively highly expressed in the posterior kidney and posterior gut. Moreover, the halibut brain showed a relatively high level of IL-6 transcripts. Anterior kidney leucocytes in vitro stimulated with imiquimod showed a significant increase in mRNA level of the five halibut cytokine genes. The sequence and characterisation data presented here will be useful for further investigation of both innate and adaptive immune responses in halibut, and be helpful in the design of vaccines for the control of various infectious diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s11033-011-0969-x) contains supplementary material, which is available to authorized users.

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The role of IL&hyphen;11 in hematopoiesis as revealed by a targeted mutation of its receptor

Cited by 30 publications

References 74 publications

Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

IL-7 Induces Myelopoiesis and Erythropoiesis

Characterisation and expression analysis of the Atlantic halibut (Hippoglossus hippoglossus L.) cytokines: IL-1β, IL-6, IL-11, IL-12β and IFNγ

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