Thymic Stromal Lymphopoietin Receptor-Mediated IL-6 and CC/CXC Chemokines Expression in Human Airway Smooth Muscle Cells: Role of MAPKs (ERK1/2, p38, and JNK) and STAT3 Pathways

Shan, Lianyu; Redhu, Naresh Singh; Saleh, Anas; Halayko, Andrew J.; Chakir, Jamila; Gounni, Abdelilah S.

doi:10.4049/jimmunol.0902515

Cited by 111 publications

(106 citation statements)

References 59 publications

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“…More recently, three groups showed that two members of the Janus family kinases, Jak1 and Jak2 are activated in TSLP signaling (29 -31). Erk1/2, JNK1/2, and p38 have also been reported as intermediates in TSLP signaling (29,32). In agreement with these reports, our proteomic data indicates that Jak2, Erk1/2, JNK1/2, and p38 were all indeed inducibly phosphorylated by TSLP stimulation.…”

Section: Btk Protein Tyrosine Kinasesupporting

confidence: 91%

“…TSLP requires JAK1 and JAK2 to activate STAT5 (31). TSLP is also known to increase the phosphorylation of ERK1/2, JNK1/2, AKT, ribosomal protein S6, and 4E-BP1 (12,29,32,33). However, the knowledge of TSLP signaling obtained from biochemical experiments is scattered and the detailed signal transduction pathways responsible for various biological effects of TSLP still remain elusive.…”

Section: Thymic Stromal Lymphopoietin (Tslp)mentioning

confidence: 99%

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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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Section: Btk Protein Tyrosine Kinasesupporting

confidence: 91%

Section: Thymic Stromal Lymphopoietin (Tslp)mentioning

confidence: 99%

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Zhong

Kim

Chaerkady³

et al. 2012

Molecular & Cellular Proteomics

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“…3b and c) contain STAT3 and EGFR, among others. STAT3 has been shown to be involved as a transcriptional mechanism for thymic stromal lymphopoietin to induce a proinflammatory gene expression in ASM cells [30], whereas blocking EGFR may lead to a reduction in mucus hypersecretion [31]. Taken together, these results indicate that the regulation of biological processes in the airways is evidently different in asthma compared to controls.…”

Section: Discussionmentioning

confidence: 94%

Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthmaversuscontrols

Yick

Zwinderman²,

Kunst

et al. 2013

Eur Respir J

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The cellular and molecular pathways in asthma are highly complex. Increased understanding can be obtained by unbiased transcriptomic analysis (RNA-Seq). We hypothesised that the transcriptomic profile of whole human endobronchial biopsies differs between asthma patients and controls.First, we investigated the feasibility of obtaining RNA from whole endobronchial biopsies suitable for RNA-Seq. Secondly, we examined the difference in transcriptomic profiles between asthma and controls. This cross-sectional study compared four steroid-free atopic asthma patients and five healthy nonatopic controls. Total RNA from four biopsies per subject was prepared for RNA-Seq. Comparison of the numbers of reads per gene in asthma and controls was based on the Poisson distribution.46 genes were differentially expressed between asthma and controls, including pendrin, periostin and BCL2. 10 gene networks were found to be involved in cellular morphology, movement and development.RNA isolated from whole human endobronchial biopsies is suitable for RNA-Seq, showing different transcriptomic profiles between asthma and controls. Novel and confirmative genes were found to be linked to asthma. These results indicate that biological processes in the airways of asthma patients are regulated differently when compared to controls, which may be relevant for the pathogenesis and treatment of the disease. @ERSpublications Transcriptome sequencing shows processes in the airways of asthmatics are differently regulated at transcriptomic level

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“…TSLP induces IL-6 expression and is linked to asthma, chronic obstructive pulmonary disease, and atopic dermatitis [64]. IL-6 promotes a chronic inflammatory response by stimulating T-cells and B-cells [65].…”

Section: Inflammation and Cytokinesmentioning

confidence: 99%

Is there a link between autism and glyphosate-formulated herbicides?

Beecham¹,

Seneff²

2016

J Autism

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Glyphosate is the most widely used herbicide on the planet, and its increasing use over time in the United States aligns well with the increasing rates of autism determined by the Centers for Disease Control. Based on the known mechanism of glyphosate toxicity, we hypothesize that a pregnant woman's exposure at midpregnancy to glyphosate-formulated herbicides (GFH) may produce, in her unborn child's brain, anatomic alterations of cortical neuron layering remarkably similar to those found in the brains of humans with autism. Glyphosate's known ability to chelate manganese ions combined with evidence of severely depleted serum manganese in cows exposed to glyphosate makes it likely that glyphosate would induce manganese deficiency in humans, interfering with the function of manganese-dependent enzymes. In particular, this would affect the maternal pituitary's manganese-dependent Protein Phosphatase 1 (PP1) enzyme, resulting in a significant reduction in maternal serum levels of Thyroid-Stimulating Hormone (TSH). A study of mid-pregnancy maternal TSH serum levels in human mothers has found a statistical correlation of reduced TSH to increased risk of autism in offspring. Since insufficient thyroid stimulation by TSH or by iodine deficiency would both induce hypothyroidism, effects of iodine deficiency can be expected to emulate effects of TSH deficiency. Cortical neuron disarrangements have been produced in the brains of offspring of rat dams fed an iodine-deficient diet, and such foci of disordered cortical neurons are characteristically found in human autistic brains. While the research literature on glyphosate's endocrine disrupting effects is limited, diverse evidence from animal studies reveals effects that suggest impaired thyroid function. If our hypothesis can be substantiated by a focused research effort, it would provide further justification for reducing or, ideally, eliminating glyphosate-formulated herbicide exposures in pregnant women.

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Thymic Stromal Lymphopoietin Receptor-Mediated IL-6 and CC/CXC Chemokines Expression in Human Airway Smooth Muscle Cells: Role of MAPKs (ERK1/2, p38, and JNK) and STAT3 Pathways

Cited by 111 publications

References 59 publications

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthmaversuscontrols

Is there a link between autism and glyphosate-formulated herbicides?

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