Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation

Quentmeier, Hilmar; Drexler, Helmut; Fleckenstein, Diana; Zaborski, Margarete; Armstrong, Allison; Sims, John E.; Sd, Lyman

doi:10.1038/sj.leu.2402175

Cited by 175 publications

(149 citation statements)

References 24 publications

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“…Although TSLP has been associated with inflammatory responses, the factors that regulate its expression remain unclear. Studies showed that epithelial cells, primarily in the lung, skin, and gut, are the primary sources of TSLP in humans (7). Because AECs in human asthmatics were found to have increased TSLP mRNA (11), and TSLP levels in the lungs of mice with antigen-induced airway inflammation displayed elevated TSLP levels (12), we chose to study the regulation of TSLP gene expression in AECs.…”

Section: Il-1␤ and Tnf-␣ Induce Human Tslp Expression From Normal Humanmentioning

confidence: 99%

“…The TSLP receptor complex is a heterodimer that consists of a low-affinity ligand binding chain, the TSLP receptor (TSLPR), and the IL-7 receptor ␣ chain (IL-7R␣) (5,6). TSLP and TSLPR have also been identified and characterized in humans, and the human TSLP receptor complex has been shown to also be a heterodimer that is composed of the TSLPR and IL-7R␣ chains (7,8). Although the degree of sequence homology between human and mouse TSLP and between human and mouse TSLPR is quite low (43% and 39%, respectively), the expression profiles are similar in the two species, with B cells and CD11c ϩ dendritic cells being the primary cell populations expressing the TSLPR (ref.…”

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confidence: 99%

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Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

Lee¹,

Ziegler

2007

Proc. Natl. Acad. Sci. U.S.A.

312

315

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The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1␤ and TNF-␣ were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo ؊ and A549, and showed that IL-1␤-and TNF-␣-mediated human TSLP promoter activation in these cells was mediated by an upstream NF B site. Mutation of this NF B site abolished activation, as did overexpression of a dominant-negative version of I B kinase (IKK)␤ (a kinase acting on I B, the inhibitor of NF B). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NF B in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NF B site that was also critical for IL-1␤-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1␤ and TNF-␣ regulate human TSLP gene expression in an NF B-dependent manner.proinflammatory cytokine ͉ T helper 2 inflammation ͉ transcriptional regulation T hymic stromal lymphopoietin (TSLP) is a cytokine that was originally identified in culture supernatants of a mouse thymic stromal cell line and has been shown to support the development of pre-B cells to B220 ϩ IgM ϩ immature B cells (1-4). The TSLP receptor complex is a heterodimer that consists of a low-affinity ligand binding chain, the TSLP receptor (TSLPR), and the IL-7 receptor ␣ chain (IL-7R␣) (5, 6). TSLP and TSLPR have also been identified and characterized in humans, and the human TSLP receptor complex has been shown to also be a heterodimer that is composed of the TSLPR and IL-7R␣ chains (7,8). Although the degree of sequence homology between human and mouse TSLP and between human and mouse TSLPR is quite low (43% and 39%, respectively), the expression profiles are similar in the two species, with B cells and CD11c ϩ dendritic cells being the primary cell populations expressing the TSLPR (ref. 9 and S.F.Z. and D. R. J. Rawlings, unpublished results). TSLP is produced primarily by epithelial cells in the lungs, gut, and skin (8). Recent work (e.g., refs. 10 and 11) has shown that TSLP levels are increased at sites of inflammation. For example, lesional skin from patients with atopic dermatitis displayed markedly elevated TSLP expression, whereas uninvolved skin did not (10). Similarly, airway epithelium from asthmatics showed increased TSLP mRNA expression (11) and supported a role for TSLP in promoting T helper 2-type allergic inflammation. CD4 ϩ T cells, primed by TSLP-treated dendritic cells, produce the proallergic cy...

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Section: Il-1␤ and Tnf-␣ Induce Human Tslp Expression From Normal Humanmentioning

confidence: 99%

mentioning

confidence: 99%

Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

Lee¹,

Ziegler

2007

Proc. Natl. Acad. Sci. U.S.A.

312

315

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“…Stat5 was the first molecule that was shown to be phosphorylated by TSLP stimulation in both human and murine systems (2,63,95). Brown et al showed that TSLP could induce the phosphorylation of ribosomal protein S6 and 4E-BP1 in leukemic cells (33).…”

Section: Btk Protein Tyrosine Kinasementioning

confidence: 99%

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Zhong

Kim

Chaerkady³

et al. 2012

Molecular & Cellular Proteomics

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Thymic stromal lymphopoietin (TSLP) is a cytokine that plays diverse roles in the regulation of immune responses. TSLP requires a heterodimeric receptor complex consisting of IL-7 receptor ␣ subunit and its unique TSLP receptor (gene symbol CRLF2) to transmit signals in cells. Abnormal TSLP signaling (e.g. overexpression of TSLP or its unique receptor TSLPR) contributes to the development of a number of diseases including asthma and leukemia. However, a detailed understanding of the signaling pathways activated by TSLP remains elusive. In this study, we performed a global quantitative phosphoproteomic analysis of the TSLP signaling network using stable isotope labeling by amino acids in cell culture. By employing titanium dioxide in addition to antiphosphotyrosine antibodies as enrichment methods, we identified 4164 phosphopeptides on 1670 phosphoproteins. Using stable isotope labeling by amino acids in cell culture-based quantitation, we determined that the phosphorylation status of 226 proteins was modulated by TSLP stimulation. Our analysis identified activation of several members of the Src and Tec families of kinases including Btk, Lyn, and Tec by TSLP for the first time. In addition, we report TSLP-induced phosphorylation of protein phosphatases such as Ptpn6 (SHP-1) and Ptpn11 (Shp2), which has also not been reported previously. Co-immunoprecipitation assays showed that Shp2 binds to the adapter protein Gab2 in a TSLP-dependent manner. This is the first demonstration of an inducible protein complex in TSLP signaling. A kinase inhibitor screen revealed that pharmacological inhibition of PI-3 kinase, Jak family kinases, Src family kinases or Btk suppressed TSLP-dependent cellular proliferation making them candidate therapeutic targets in diseases resulting from aberrant TSLP signaling. Our study is the first phosphoproteomic analysis of the TSLP signaling pathway that greatly expands our understanding of TSLP signaling and provides novel therapeutic targets for TSLP/ TSLPR-associated diseases in humans. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.017764, 1-22, 2012. Thymic stromal lymphopoietin (TSLP)1 is an IL-7-like fourhelix bundle cytokine that was originally identified as a growth factor from the conditioned medium of the Z210R.1 thymic stromal cell line to support B-cell development in the absence of IL-7 (1, 2). TSLP mediates its effects through a heterodimeric receptor complex consisting of IL-7R␣ and a unique TSLP receptor (TSLPR, also known as CRLF2) (3, 4). In humans, epithelial cells are the major source of TSLP (5), which acts on a number of distinctive cell types. TSLP released from airway epithelial cells synergizes with IL-1 and TNF to stimulate the production of high levels of Th2 cytokines by mast cells (6). TSLP can promote the maturation of dendritic cells, thereby driving the Type 2 differentiation of T helper cells (7). Studies have also shown that TSLP enhances proliferation of CD4ϩ and CD8ϩ T cells activated by T-cell receptor stimulation (8, 9). In mice, TSLP can also activ...

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“…[10][11][12][13] The low homologies of murine versus human TSLP and CRLF2 (approx. 40%) 14,15 suggest the need for novel models to study the in vivo role of TSLP in normal and malignant human B lymphopoiesis.…”

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confidence: 99%

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

et al. 2015

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T hymic stromal lymphopoietin (TSLP) stimulates in vitro proliferation of human fetal B-cell precursors. However, its in vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2.

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Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation

Cited by 175 publications

References 24 publications

Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

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