Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome

Tangye, Stuart G.; Cook, Matthew C.; Fulcher, David A.

doi:10.4049/jimmunol.182.1.21

Cited by 51 publications

(40 citation statements)

References 87 publications

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“…Patients with AD-HIES have been instrumental in uncovering the role of STAT3 in the development of cellular immune responses (16,41,42). With these patients, we were able to explore the influence of STAT3 on the life cycle of a globally relevant, persistent virus in humans.…”

Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Hill

Koganti

Zhi

et al. 2013

J Virol

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g Lytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBVinfected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis. E pstein-Barr virus (EBV) infects most humans and persists silently in B lymphocytes. Primary infection with EBV can cause infectious mononucleosis (IM). Under certain circumstances, EBV can cause B-cell lymphomas and epithelial cell cancers (1). Several studies suggest that EBV lytic activation is an important step in the pathogenesis of such EBV-related diseases (2-5). From a therapeutic standpoint, efforts to eliminate EBV-positive tumors using nucleoside analogues after induction of viral lytic activation have shown promise (6-8). However, EBV-infected tumor cells are not fully permissive to lytic induction, as only a fraction of EBV-infected B cells exposed to lytic cycle-inducing agents enters the lytic cycle; the remainder of the population is refractory to lytic induction (9, 10). These refractory cells are not susceptible to oncolytic therapy, necessitating further investigations into the physiology underlying both lytic and refractory states.A general problem with investigating EBV lytic activation is that a mixed population of refractory and lytic cells results from exposure to lytic cycle-inducing stimuli. We therefore developed a technique to separate lytic cells from refractory cells in a mixed population of EBV-infected B cells (9). Our previous studies using this technique showed that host cell determinants regulate susceptibility of EBV-infected B cells to lytic cycle-inducing stimuli (9, 11) and that higher levels o...

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Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Hill

Koganti

Zhi

et al. 2013

J Virol

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“…It is well known that Stat3 system participates in the immune system. 35) Since interferon treatment for hepatitis causes depression, there is some interest among Stat3 system, immune system, and the depression.…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of Signal Transducers and Activators of Transcription 3 System on Depression in the Model Mice Brain

Mingmalairak

Tohda

Murakami

et al. 2010

Biological & Pharmaceutical Bulletin

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Although available evidence from neurobiological studies consistently indicates that depression phenotypes are the outcome of a combination of genetic and environmental factors, 1,2) little is known about the pathophysiology of depression. A large number of clinical observations have suggested that stress is a predisposing factor involved in the onset of affective disorders, especially depression. [3][4][5] Most animal models of depression are based on behavioral deficits induced by a variety of stress paradigms. One of the most commonly used animal models of depression is a learned helplessness (LH) paradigm. In this paradigm, animals previously exposed to inescapable shock are subsequently less able to escape from shock than control animals. Animals with LH behavior exhibit impairments of behavioral, biochemical, physiological and hormonal parameters somewhat similar to those observed in patients with depressive disorders for several days.2,6-8) Interestingly, however, only 10-80% of animals exposed to inescapable shock develop LH behaviors. [9][10][11] The variability of responses in these animals may be due to several factors including procedures and condition of the induction of LH behaviors, the criteria used for defining LH behaviors 11) and also genetic variation. When we think about the variation from another viewpoint, clarifying the reason for this may give us information about endogenous factors that are involved in generation of depressive disorders. Therefore, in this article, we divided stressed animals into two groups which presented a symptom of depression and which did not show it, artificially, and examined the gene expression changes between.We previously found that antidepressant drugs and a traditional Chinese and Japanese prescription (Wakan-yaku) with antidepressant-like action enhances expression of BCL2/adenovirus E1B 19kD-interacting protein 3 (BNIP3) mRNA in a cultured cell line NG108-15. Our results suggest that BNIP3 is a candidate intrinsic factor related to antidepressive effects of these drugs.12) We also found that BNIP3 mRNA expression is upregulated by stress exposure and BNIP3 may be involved in imipramine-induced amelioration of depressive state of LH mouse brain.13) Using this model animal brain, it seems possible to find novel depressive factors in addition to BNIP-3.Microarray technology vastly improved brain research when it arrived some years ago and has become a very useful tool for identification of genes and molecular pathways involved in psychiatric disorders. [14][15][16] Further to understand the pathophysiology of depression, accumulation of gene expression analyses based on the phenotypic variability of animals exposed to stress is needed. In the present study, we investigated the expression of genes associated with the pathogenesis of depressive disorders using DNA microarray technique in the LH mice frontal cortex. Genes that were down-regulated or up-regulated were examined in detail by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR...

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“…Meanwhile, an oral inhibitor that suppresses STAT3/5 phosphorylation is undergoing phase II testing for the same indication in Japan and shows efficacy in various blood-borne cancers that are driven by STAT3 or STAT5 (72). Although the complete absence of STAT3 is associated with impaired immune response, the existence of naturally occurring germline-null mutations in STAT3 in humans, suggest that the associated Hyper IgE syndrome only occurs if STAT3 activity is below 25% (73). On the other hand, systemic ablation of one STAT3 allele is sufficient to impair tumor growth in the stomach of gp130 Y757F mice (74) and also to reduce colonic tumor burden that arise in response to mutations in Apc (71).…”

Section: Stat3 Inhibitionmentioning

confidence: 99%

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

Ernst

Putoczki

2014

Clinical Cancer Research

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Emerging evidence suggests that cytokines produced by inflammatory cells act as rheostats to link the degree of wounding and local inflammation to epithelial cell survival, proliferation, and metabolism that collectively underpin the repair response. Among these cytokines, the GP130 family, which encompasses, among others, IL6 and IL11, plays a major role in orchestrating these complex processes through the activation of the latent signal transducer and activator of transcription 3 (STAT3) in the epithelium. However, many of the molecular mechanisms that govern and ensure effective epithelial wound healing and regeneration renewal also promote tumorigenesis and the progression of established cancers. Accordingly, GP130 cytokines endow the inflammatory tumor microenvironment with a capacity to promote "cancer hallmark capabilities" of the malignant epithelium, while simultaneously suppressing the antitumor response of innate and adaptive immune cells. Here, we review some recent insights derived from genetic and therapeutic inhibition of the IL6/IL11-GP130-STAT3 signaling cascade in the context of preclinical mouse models of cancer, which are likely to have implications to other solid malignancies. Clin Cancer Res; 20(22); 5579-88. Ó2014 AACR.

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Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome

Cited by 51 publications

References 87 publications

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Possible Involvement of Signal Transducers and Activators of Transcription 3 System on Depression in the Model Mice Brain

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

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