Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

Mangan, James K.; Tantravahi, Ramana; Rane, Sushil G.; Reddy, E. Premkumar

doi:10.1038/sj.onc.1209280

Cited by 12 publications

(8 citation statements)

References 47 publications

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“…1 D ). Of note, Jak3 is a well-known STAT3 target gene (ref (31) and data not shown), while upregulation of IRF4 was previously reported to coincide with the appearance of pre-PB in mouse B cells (2). …”

Section: Resultsmentioning

confidence: 80%

IL-21 and CD40L Synergistically Promote Plasma Cell Differentiation through Upregulation of Blimp-1 in Human B Cells

Ding

Chen

et al. 2013

The Journal of Immunology

129

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After undergoing Ig somatic hypermutation and antigen selection, germinal center (GC) B cells terminally differentiate into either memory or plasma cells (PCs). It is known that the CD40L and IL-21/STAT3 signaling pathways play critical roles in this process, yet it is unclear how the B cell transcription program interprets and integrates these two types of T cell derived signals. In this study, we characterized the role of STAT3 in the GC-associated PC differentiation using purified human tonsillar GC B cells and a GC B cell-like cell line. When primary GC B cells were cultured under PC differentiation condition, STAT3 inhibition by AG490 prevented the transition from GC centrocytes to pre-plasmablast (pre-PB) suggesting that STAT3 is required for the initiation of PC development. In a GC B cell-like human B cell line, although IL-21 alone can induce low-level Blimp-1 expression, maximum Blimp-1 upregulation and optimal PC differentiation required both IL-21 and CD40L. CD40L, while having no effect on Blimp-1 as a single agent, greatly augmented the amplitude and duration of IL-21 triggered Jak-STAT3 signaling. In the human PRDM1 locus, CD40L treatment enhanced the ability of STAT3 to upregulate Blimp-1 by removing BCL6, a potent inhibitor of Blimp-1 expression, from a shared BCL6/STAT3 site in intron 3. Thus, IL-21 and CD40L collaborate through at least two distinct mechanisms to synergistically promote Blimp-1 activation and PC differentiation.

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Section: Resultsmentioning

confidence: 80%

IL-21 and CD40L Synergistically Promote Plasma Cell Differentiation through Upregulation of Blimp-1 in Human B Cells

Ding

Chen

et al. 2013

The Journal of Immunology

129

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“…A likely candidate up-or downstream is Jak3, which was induced at least from PND 14 on in the rd1 mouse and with a peak at 24 h after light exposure (Table 69.4). Since Jak3 activity is mainly regulated on the gene expression level (Mangan et al 2006), the strong induction of mRNA levels suggest a prominent role of this kinase in the injured retina. It is possible that Jak3 is part of an immune-related response induced by retinal damage.…”

Section: Discussionmentioning

confidence: 99%

The Differential Role of Jak/Stat Signaling in Retinal Degeneration

Lange

Thiersch

Samardzija

et al. 2009

Retinal Degenerative Diseases

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Retinal degenerative diseases are a major cause of severe visual impairment or blindness in humans. To develop therapeutic strategies it is of particular importance to understand the molecular mechanisms taking place during the progression of the disease. Genes and proteins of the Janus kinase/Signal Transducer and Activator of Transcription (Jak/STAT) signaling pathway have been shown to play an important role in models of retinal degeneration (RD). Here we investigated the expression of additional genes involved in the Jak/STAT pathway in an induced (light exposure) and an inherited (rd1 mouse) model of RD. We show that STAT mRNAs as well as the Jak2/shp-1 pathway are differentially regulated in the two models. In contrast, we show that Jak3 mRNA is upregulated in both, the light damaged and the degenerative retina of the rd1 mouse. This common answer to probably different apoptotic stimuli suggests a prominent role for Jak3 in the damaged retina and could therefore be interesting for further investigations.

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“…Keratin overexpression under some conditions such as cerulein-induced pancreatitis was shown to be associated with NF-B activation, suggesting a role for NF-B in the transcriptional regulation of keratin expression (51). Although the signaling pathway of keratin induction by IL-6 is not known, IL-6 is known to directly or indirectly induce Sp1 (52,53) as well as activate NF-B (29), and hence, activation of Sp1 and/or NF-B may potentially be involved in IL-6-mediated keratin expression in Caco2-BBE cells.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Induces Keratin Expression in Intestinal Epithelial Cells

Wang

Srinivasan

Theiss

et al. 2007

Journal of Biological Chemistry

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Keratin 8 (K8) and keratin-18 (K18) are the major intermediate filament proteins in the intestinal epithelia. The regulation and function of keratin in the intestinal epithelia is largely unknown. In this study we addressed the role and regulation of K8 and K18 expression by interleukin 6 (IL-6). Caco2-BBE cell line and IL-6 null mice were used to study the effect of IL-6 on keratin expression. Keratin expression was studied by Northern blot, Western blot, and confocal microscopy. Paracellular permeability was assessed by apical-to-basal transport of a fluorescein isothiocyanate dextran probe (FD-4). K8 was silenced using the small interfering RNA approach. IL-6 significantly up-regulated mRNA and protein levels of K8 and K18. Confocal microscopy showed a reticular pattern of intracellular keratin localized to the subapical region after IL-6 treatment. IL-6 also induced serine phosphorylation of K8. IL-6 decreased paracellular flux of FD-4 compared with vehicle-treated monolayers. K8 silencing abolished the decrease in paracellular permeability induced by IL-6. Administration of dextran sodium sulfate (DSS) significantly increased intestinal permeability in IL-6 ؊/؊ mice compared with wild type mice given DSS. Collectively, our data demonstrate that IL-6 regulates the colonic expression of K8 and K18, and K8/K18 mediates barrier protection by IL-6 under conditions where intestinal barrier is compromised. Thus, our data uncover a novel function of these abundant cytoskeletal proteins, which may have implications in intestinal disorders such as inflammatory bowel disease wherein barrier dysfunction underlies the inflammatory response.

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Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

Cited by 12 publications

References 47 publications

IL-21 and CD40L Synergistically Promote Plasma Cell Differentiation through Upregulation of Blimp-1 in Human B Cells

IL-21 and CD40L Synergistically Promote Plasma Cell Differentiation through Upregulation of Blimp-1 in Human B Cells

The Differential Role of Jak/Stat Signaling in Retinal Degeneration

Interleukin-6 Induces Keratin Expression in Intestinal Epithelial Cells

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