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Results for “STAT6 Transcription Factor”

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At least 19 recordsLinked to original sources

PubMed1998

T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6.

An important signaling pathway for the differentiation of T helper type 2 (TH2) cells from uncommitted CD4 T cell precursors is activation of the STAT6 transcription factor by interleukin 4 (IL-4). The protooncogene BCL-6 is also involved in TH2 differentiation, as BCL-6 -/- mice develop an inflammation of the heart and lungs associated with an overproduction of TH2 cells. Surprisingly, IL-4 -/- BCL-6 -/- and STAT6 -/- BCL-6 -/- double-mutant mice developed the same TH2-type inflammation of the heart and lungs as is characteristic of BCL-6 -/- mice. Furthermore, a TH2 cytokine response developed in STAT6 -/- BCL-6 -/- and IL-4 -/- BCL-6 -/- mice after immunization with a conventional antigen in adjuvant. In contrast to these in vivo findings, STAT6 was required for the in vitro differentiation of BCL-6 -/- T cells into TH2 cells. BCL-6, a transcriptional repressor that can bind to the same DNA binding motifs as STAT transcription factors, seems to regulate TH2 responses in vivo by a pathway independent of IL-4 and STAT6.

Animals↗

PubMed2004

STAT6 transcription factor binding sites with mismatches within the canonical 5'-TTC...GAA-3' motif involved in regulation of delta- and mu-opioid receptors.

Opioid receptors are expressed in neuronal and immune cells and regulated in response to immunological processes. Herein, we demonstrate up-regulation of the delta-opioid receptor gene by interleukin-4 in immune cells (primary T and polymorphonuclear leukocytes, Jurkat E6 T cells), and in NG 108-15 neuronal cells. We identified an interleukin-4-responsive element at nt -671 on the murine gene promoter, to which the transcription factor STAT6 binds, as shown by reporter gene analysis and STAT6/DNA interaction studies in living cells with transcription factor decoy oligonucleotides. STAT6 normally binds to palindromic DNA motifs with a 5'-TTC...GAA-3' core. Notably, the delta-opioid receptor STAT6 site (5'-TTC...GGA-3') is an imperfect palindrome with a mismatch within this core sequence. A systematic analysis of possible mismatch 5'-TTC...GAA-3' motifs revealed that STAT6 also binds to the sequence 5'-TTA...GAA-3'. This motif occurs as a polymorphism in the human mu-opioid receptor gene (Kraus et al. 2001 J. Biol. Chem 276, 43901-43908). We show that this mutated element has a significantly reduced STAT6 binding activity which correlates to its reduced interleukin (IL)-4 inducibility. In contrast, the non-canonical STAT6 site of the delta-opioid receptor binds STAT6 with similar high activity as a perfectly palindromic STAT6 site and is strongly inducible by IL-4.

Amino Acid Motifs↗

PubMed2003

Functional characterization of IL-13 receptor alpha2 gene promoter: a critical role of the transcription factor STAT6 for regulated expression.

Interleukin (IL)-4 and IL-13 are two structurally and functionally related cytokines that have overlapping but also distinct biological activities. One of the components of the IL-13 receptor, the alpha2 chain (IL-13Ralpha2), has been reported to downregulate the cell responsiveness to IL-13, without affecting IL-4 signaling. Here, we report that TNFalpha synergizes with either IL-4 or IL-13 in inducing the IL-13Ralpha2 chain at both the mRNA and protein levels in the HaCaT human keratinocyte cell line. Further studies by 5'RACE identified as yet undescribed exonic sequences of the IL-13Ralpha2 5'UTR, provided evidence for the expression of alternatively spliced IL-13Ralpha2 transcripts and defined the transcription start of the IL-13Ralpha2 gene. A 1.5 kb region upstream of the first exon of the IL-13Ralpha2 gene displayed basal promoter activity when inserted in a reporter plasmid and transiently transfected in HaCaT cells. This promoter activity was further increased in response to IL-4 and IL-13. Furthermore, by electrophoretic mobility shift assay and site-directed mutagenesis, we showed that the IL-4/IL-13-induced promoter activity depended upon a positively acting STAT6 response element. Finally, TNFalpha was shown to potentiate IL-4/IL-13-induced IL-13Ralpha2 promoter activity when the same reporter construct was studied in stably but not in transiently transfected cells. These results suggest that the synergistic effect of TNFalpha on IL-4/IL-13-induced IL-13Ralpha2 expression is dependent upon chromatin re-modeling events.

5' Flanking Region↗

PubMed1998

Interleukin-4 and -13 induce upregulation of the murine macrophage 12/15-lipoxygenase activity: evidence for the involvement of transcription factor STAT6.

When human monocytes or alveolar macrophages are cultured in the presence of interleukin (IL)-4 or IL-13, the expression of the reticulocyte-type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not expressed, but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages. To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation, we studied the regulation of the leukocyte-type 12-lipoxygenase of murine peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10. When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, suggesting pretranslational control mechanisms. In contrast, no upregulation of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6-deficient mice. Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activity was detected in heart, spleen, and lung of the transgenic animals. Moreover, a strong induction of the enzyme was observed in red cells during experimental anemia in mice. The data presented here indicate that (1) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation requires expression of the transcription factor STAT6, and (3) the constitutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed2001

Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site.

Morphine and the endogenous opioid peptide beta-endorphin exert neuromodulatory as well as immunomodulatory effects, which are transduced by mu-opioid receptors. In this report we show that stimulation with interleukin-4 induces mu-opioid receptor transcripts in human primary blood cells (T cells and polymorphonuclear leukocytes), immune cell lines (Raji, U-937, and HMEC-1), and dendritic cells. In nonstimulated immune cells this gene is silent. In addition, mu receptor transcription is up-regulated by interleukin-4 in cultures of primary rat neurons. Transient transfection experiments in Raji and SH SY5Y neuronal cells with human and rat reporter gene constructs linked the interleukin-4 effect directly to cis-active mu receptor promoter elements located at nucleotide -997 on the human gene and nucleotide -727 on the rat gene. The interleukin-4 response elements function orientation independently. They bind STAT6 transcription factors as shown by electrophoretic mobility shift assays. In the human gene, a single nucleotide polymorphism within the interleukin-4 response element reduces the trans-activating potential of this element by 50%, which may affect the phenotype of persons carrying this variation. These findings provide a molecular basis for understanding bidirectional interactions between the opioid system and the immune system.

Alleles↗

PubMed2004

Differential activation of signal transducer and activator of transcription 6 in B cells from allergic children and their non-allergic siblings.

BACKGROUND: The germline (GL) epsilon promoter is regulated by IL-4 and is essential for class switching to IgE. IL-4-induced gene expression is largely mediated through activation of latent transcription factor STAT6 (signal transducer and activator of transcription 6). OBJECTIVE: We investigated whether increased levels of IgE in allergic individuals may be associated with alteration in the level or activation of STAT6 and subsequent increase in GL epsilon promoter activity. METHODS: Electrophoretic mobility shift assay and Western blotting assays were used to investigate the level of expression and activation of STAT6 in Epstein-Barr virus (EBV)-transformed B cell lines from children with birch pollen allergy and their non-allergic siblings. The activity of the GL epsilon promoter was tested in a transient transfection assay. RESULTS: STAT6 was expressed at the same level in all B cell lines tested. In two out of five sibling pairs STAT6 was activated by IL-4 more efficiently in the allergic individuals but in the three other pairs the opposite was found. In transient transfections, no difference in IL-4-induced GL epsilon promoter function was detected, although basal promoter activity varied between allergic and healthy siblings in two out of five pairs. CONCLUSIONS: We demonstrate for the first time that upon IL-4 signalling STAT6 transcription factor activation differs in B cells from different individuals. Although we did not find any association between STAT6 activation and allergy, we do not exclude a possibility that stronger activation of this transcription factor is associated with an expression of allergic phenotype.

Adolescent↗

PubMed2000

In vivo expression of signal transducer and activator of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic rhinitis: effect of topical corticosteroids.

BACKGROUND: The allergen-induced late nasal response is associated with a high local expression of interleukin (IL) -4, a TH2-type cytokine implicated in immunoglobulin (Ig) E production, tissue eosinophilia and other events considered to be relevant to allergic inflammation. Interaction of IL-4 with its receptor activates at least two distinct signalling pathways that culminate in the transcription of specific target genes. One pathway involves the activation of a transcription factor termed signal transducer and activator of transcription factor 6 (STAT6). OBJECTIVE: To investigate the expression of STAT6 in the allergen-induced late nasal response and to examine the effect of local steroid treatment on STAT6 expression. METHODS: Inferior turbinate biopsies were obtained from subjects with allergic rhinitis out of the allergen season. Subjects were then randomized into topical steroid- (n = 6) and placebo-treated (n = 6) groups in a double-blind fashion. After a 6-week treatment period, a second nasal biopsy was performed 24 h after local challenge with allergen. STAT6 immunoreactivity was examined in biopsy specimens by immunocytochemistry using a specific monoclonal antibody. Numbers of inflammatory cells (CD3+ T cells and MBP+ eosinophils) and IL-4 mRNA+ cells were investigated by immunocytochemistry and in situ hybridization, respectively. RESULTS: STAT6 immunoreactivity was detected in all biopsies studied and localized predominantly to inflammatory tissue of the nasal mucosa. After allergen challenge, expression of STAT6 was markedly increased in placebo-treated patients (P < 0.01). By confocal microscopy, STAT6 was localized to the cytoplasm and the nucleus of positively-staining cells. The allergen-induced increase in STAT6 immunoreactive cells was not observed in the steroid-treated patients. The change in STAT6 immunoreactivity after allergen challenge correlated significantly with the change in numbers IL-4 mRNA+ cells (r = 0.74, P = 0.006) and CD3+ T cells (r = 0.76, P = 0. 004), but not MBP+ eosinophils. CONCLUSION: This study provides the first evidence of increased STAT6 expression in vivo in human allergic inflammation. The results support a role for STAT6 and IL-4 in the pathogenesis of late nasal response and show that decreases in STAT6 expression parallel the reduction in IL-4 expression that occurs with topical steroid treatment.

Administration, Intranasal↗

PubMed1998

A conditionally active form of STAT6 can mimic certain effects of IL-4.

Binding of IL-4 to its cognate receptor leads to the activation of a number of signaling pathways within the cell. Activation of the transcription factor STAT6 by JAK family protein tyrosine kinases has been shown to be essential for the full response of cells to IL-4. To elucidate the role of STAT6 in IL-4 signaling, we have constructed and expressed in cells a conditionally active form of the protein (STAT6:ER*) by fusing STAT6 to a modified form of the hormone-binding domain of the estrogen receptor. Activation of STAT6:ER* by 4-hydroxytamoxifen leads to specific activation of STAT6-regulated gene expression including the activation of a STAT6 reporter construct and induction of CD23 in B cell lines. Interestingly, in contrast to native STAT6, activation of STAT6:ER* occurs in the absence of detectable tyrosine phosphorylation of the fusion protein. This type of conditional system will be helpful in dissecting the mechanisms and specificity of transcriptional regulation by the STAT family of transcription factors.

Animals↗

PubMed2001

Specific inhibition of interferon signal transduction pathways by adenoviral infection.

Adenoviral evolution has generated strategies to resist host cell antiviral systems, but molecular mechanisms for evasion of interferon (IFN) effects by adenoviruses during late-phase infection are poorly defined. In this study, we examined adenovirus type 5 (AdV) effects on IFN-gamma-dependent gene expression and Janus family kinase-signal transducer and activator of transcription signaling components in human tracheobronchial epithelial cells. We found that AdV infection specifically inhibited IFN-gamma-dependent gene expression in airway epithelial cells without evidence of epithelial cell injury or generation of a soluble extracellular inhibitor. Furthermore, infection with AdV for 18-24 h blocked phosphorylation/activation of the Stat1 transcription factor that regulates IFN-gamma-dependent genes. Although AdV also inhibited IFN-alpha-dependent phosphorylation of Stat1 and Stat2, interleukin-4-dependent phosphorylation of the related transcription factor Stat6 was not affected, indicating that the virus selectively affected specific signaling pathways. Our results indicate that AdV inhibition of the IFN-gamma signal transduction cascade occurs through loss of ligand-induced receptor complex assembly and consequent component phosphorylation and suggest that lack of complex assembly is due to decreased expression of the IFN-gammaR2 chain of the IFN-gamma receptor. IFN-gammaR2 is required at an early step in Janus family kinase-signal transducer and activator of transcription pathway activation and is expressed at low levels in airway epithelial cells, supporting the concept that adenoviral down-regulation of the level of this IFN-gamma receptor component allows for persistent modulation of IFN-gamma-dependent gene expression.

Adenoviridae↗

PubMed2005

Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes.

BACKGROUND: Immune responses characterized by T H 2 type cells and IgE are important for the development of asthma and atopy. The transcription factors STAT6, GATA3, and STAT4 mediate the cytokine-induced development of naive CD4 + T cells into either T H 1 or T H 2 type. OBJECTIVE: We studied genetic variation of the STAT6, GATA3, and STAT4 genes and examined whether single nucleotide polymorphisms (SNPs) in these loci were associated with asthma or serum high IgE levels in the Finnish asthmatic families. METHODS: With denaturing high-performance liquid chromatography we screened all exons and exon-intron boundaries of the genes in 14 to 22 patients. All identified SNPs were genotyped in 120 nuclear families, and the haplotypes were analyzed by Haplotype Pattern Mining based statistical analysis. When potential association was observed, the analysis was replicated among 245 asthmatic patients and 405 population-based control subjects. RESULTS: A total of 23 SNPs were identified, of which 8 were not previously listed in the SNP database. Interestingly, a haplotype analysis of GATA3 showed 3 related haplotypes that associated with different asthma and atopy related phenotypes among both the family and case-control data sets. For STAT6 and STAT4, no significant association to asthma or serum total IgE levels was observed. CONCLUSIONS: We identified a panel of novel SNPs in genes coding for proteins important in the T H 1/T H 2 cell differentiation. SNPs of the GATA3 gene showed an initial association to asthma-related phenotypes. Elucidation of the importance of the identified panel of SNPs in other T H 1/T H 2 mediated diseases will be of great interest.

Adult↗

PubMed1999

IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and -independent mechanisms.

IL-4 promotes allergic responses and inhibits the production of proinflammatory cytokines by monocytes and macrophages. The promotion of allergic responses by IL-4 has been shown to be absolutely dependent on the transcription factor STAT6. We report here that the inhibitory effects of IL-4 on the production of TNF-alpha or IL-12 by macrophages had both STAT6-dependent and -independent components, depending on the stimuli. IL-4 failed to inhibit the release of TNF-alpha or IL-12 from STAT6 null macrophages stimulated with LPS alone. However, IL-4 still induced significant inhibition of the production of TNF-alpha and IL-12 from STAT6 null macrophages that were stimulated with the more physiologically relevant combination of LPS and IFN-gamma. These data show that STAT6 is required for the IL-4-mediated inhibition of the production of TNF-alpha and IL-12 stimulated by LPS alone, but that IL-4 also activates distinct, STAT6 independent mechanism(s) that inhibit the IFN-gamma-mediated enhancement of IL-12 and TNF-alpha production.

Adjuvants, Immunologic↗

PubMed2001

IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB.

IL-4, an anti-inflammatory cytokine, inhibits osteoclast differentiation, but the basis of this effect has been unclear. Osteoclastogenesis requires activation of RANK, which exerts its biologic effect via activation of NF-kappaB. NF-kappaB activation is manifested by nuclear translocation and binding to DNA, events secondary to phosphorylation and dissociation of IkappaBalpha. It is shown here that IL-4 reduces NF-kappaB nuclear translocation by inhibiting IkappaB phosphorylation, thus markedly inhibiting NF-kappaB DNA binding activity and blocking osteoclastogenesis entirely. Residual translocation of NF-kappaB in the presence of IL-4, however, suggests that nuclear mechanisms must primarily account for inhibition of NF-kappaB DNA binding and blockade of osteoclastogenesis. To address this issue, this study examined whether IL-4-induced STAT6 transcription factor blocks NF-kappaB transactivation. The results show that excess unlabeled consensus sequence STAT6, but not its mutated form, inhibits NF-kappaB binding. Furthermore, exogenously added STAT6 protein inhibits NF-kappaB/DNA interaction. Further supporting a role for STAT6 in this process are the findings that IL-4 fails to block osteoclastogenesis in STAT6(-/-) mice but that this blockade can be restored with addition of exogenous STAT6. Thus, IL-4 obliterates osteoclast differentiation by antagonizing NF-kappaB activation in a STAT6-dependent manner.

Animals↗

PubMed2006

Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells.

Vascular calcification is characterized by cellular transdifferentiation and expression of bone-related matrix proteins that result in the presence of bone-like structures in the vascular wall. Interleukin (IL)-4, a pleiotropic cytokine, and osteoprotegerin (OPG), an essential regulator of osteoclast biology, have both been linked to vascular disease. Here, we assessed the role of IL-4 and OPG in vascular calcification in vitro. IL-4 induced OPG mRNA levels and protein secretion by 5-fold in a dose- and time-dependent fashion in human coronary artery smooth muscle cells (CASMC). Activation of the transcription factor STAT6 preceded IL-4-induced OPG expression, and blockade of IL-4-induced STAT6 activation by the phospholipase C inhibitor D609 decreased OPG expression. Long-term exposure of IL-4 for 4 weeks resulted in transformation of CASMC towards an osteoblastic phenotype, based on the expression of the transcription factor Cbfa1 and increased mineral deposition. Notably, calcification of CASMC was inhibited by gene silencing of Cbfa1. During osteogenic transformation, IL-4 down-regulated OPG production in CASMC. IL-4 has differential effects in CASMC: While short-term exposure enhances OPG production through a STAT6-dependent mechanism, long-term exposure causes Cbfa1-dependent osteogenic transformation and a decreased production of OPG, an inhibitor of bone resorption.

Bone Resorption↗

PubMed2001

Specific inhibition of interleukin-4-dependent Stat6 activation by an intracellularly delivered peptide.

The transcription factor Stat6 (signal transducer and activator of transcription 6) is activated following stimulation with interleukin (IL)-4 or IL-13. Stat6 binds via a single SH2 domain first to tyrosine-phosphorylated motifs in the IL-4Ralpha chain, and then to another Stat6 molecule, which results in the formation of active dimers. We show here that a peptide derived from the Stat6-binding region of IL-4Ralpha (Stat6BP) is an effective inhibitor when it is delivered into cells by coupling with a membrane-permeable peptide. Stat6BP completely inhibited IL-4 dependent phosphorylation of Stat6, as well as basal and IL-4 stimulated transcription from a reporter gene construct with a Stat6-dependent promoter, while IL-3 and IL-4 dependent phosphorylation of Stat5 was not affected. The inhibitory effect of Stat6BP was transient, but could be prolonged by treating the cells with the phosphatase inhibitor pervanadate.

Antennapedia Homeodomain Protein↗

PubMed1999

p300/CBP is required for transcriptional induction by interleukin-4 and interacts with Stat6.

Interleukin-4 (IL-4) induces tyrosine phosphorylation of the latent transcription factor Stat6, which mediates the transcriptional responses of IL-4. The transactivation domain of Stat6 has recently been mapped to the C-terminal region of Stat6. We have investigated the mechanism by which Stat6, through its transactivation domain, induces transcription. Previous studies have shown that diverse regulated transcription factors interact with coactivators such as p300 and CBP. We report that Stat6 used the interaction with p300/CBP to exert its stimulatory effects. Overexpression of p300/CBP increased IL-4-induced transcription of Stat6 activated reporter genes. The requirement of p300/CBP for Stat6-mediated transactivation is shown by coexpression of the adenovirus E1A protein. E1A repressed the IL-4-induced reporter gene activity, while mutants of E1A, which do not interact with p300/CBP, failed to block the IL-4-induced response. In addition, we found that the minimal transactivation domain of Stat6, when fused to the GAL4 DNA-binding domain, was repressed by E1A, whereas the fusion protein p300-VP16 increased the transcriptional activity. In two-hybrid protein interaction assays in mammalian cells, we mapped the interaction domain of CBP to a C-terminal region between amino acids 1850 and 2176, a region distinct from the interaction domain of CBP with Stat1, Stat2 or Stat5. Finally, we show that antibodies raised against p300 coimmunoprecipitated Stat6 and p300 from transfected COS7 cells and antibodies against Stat6 coimmunprecipitated endogenous Stat6 and CBP from Ba/F3 cells. Our data suggest that the transactivation domain of Stat6 makes contact with the basal transcription machinery by binding to p300/CBP.

Animals↗

PubMed2002

The CD23b promoter is a target for NF-AT transcription factors in B-CLL cells.

CD23 is atypically highly expressed in various chronic diseases, including B-CLL, lupus erythematodes and rheumatoid arthritis. Its expression can be further enhanced by interleukin 4 (IL-4). We have shown before that in B-CLL cells nuclear factor(s) of activated T cells (NF-ATs) show permanent nuclear localization and therefore constitutive transcriptional activity. Here we identify CD23b promoter as a novel target for NF-AT factors in B-CLL cells. The CD23b promoter contains two NF-AT binding sites to which NF-ATp and NF-ATc factors bind with high affinity. Mutations introduced into these sites abolished NF-AT binding and impaired the promoter activity, as did cyclosporin A (CsA), an inhibitor of nuclear transport of NF-ATs. Furthermore, we show that IL-4-induced transcription factor STAT6 cooperates with NF-ATs in the induction of the CD23b promoter activity. These results show that the CD23b promoter is a target for NF-AT factors and suggest that the cooperation between NF-AT and STAT factors might be one of the molecular mechanisms responsible for high-level expression of CD23 on the surface of B-CLL cells.

Base Sequence↗

PubMed1996

Antigen-receptor engagement in B cells induces nuclear expression of STAT5 and STAT6 proteins that bind and transactivate an IFN-gamma activation site.

The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor receptors in a number of cell types, and binds to a consensus sequence defined in part by the IFN-gamma activation site (GAS). It is not known whether these transcription factors respond to other kinds of growth stimuli, and, with particular relevance to lymphocytes, it is not known whether STAT proteins participate in Ag-specific responses. To determine the role of STAT proteins, coupling between Ag-receptor cross-linking and nuclear expression of DNA-binding protein complexes that recognize GAS sequences was evaluated. Ag-receptor triggering in primary B lymphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distinguished by electrophoretic mobility and GAS preference from IRF-1 GAS-binding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS-binding activity by sIg was inhibited by the tyrosine kinase inhibitor, herbimycin A, and binding activity was eliminated by tyrosine phosphatase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induced by sIg engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated with cytokine signaling is triggered in B lymphocytes through Ag-receptor engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses.

Animals↗

PubMed2004

Kit and FcepsilonRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells.

In human mast cells, derived from CD34(+) peripheral blood cells, we observed that Kit ligand (KL) failed to induce degranulation but acted in synergy with antigen to markedly enhance degranulation, levels of cytokine gene transcripts, and production of cytokines. Further examination revealed that antigen and KL activated common and unique signaling pathways to account for these varied responses. KL, unlike antigen, failed to activate protein kinase C but activated phospholipase Cgamma and calcium mobilization and augmented these signals as well as degranulation when added together with antigen. Both KL and antigen induced signals that are associated with cytokine production, namely phosphorylation of the mitogen-activated protein kinases, phosphatidylinositol 3-kinase-dependent phosphorylation of protein kinase B (also known as Akt), and phosphorylation of nuclear factor kappaB (NFkappaB). However, only KL stimulated phosphorylation of signal transducer and activator of transcription 5 (STAT5) and STAT6, whereas antigen weakly stimulated the protein kinase C-dependent induction and phosphorylation of c-Jun and associated activating protein-1 (AP-1) components, an action that was markedly potentiated by costimulation with KL. Interestingly, most signals were down-regulated on continuous exposure to KL but were reactivated along with cytokine gene transcription on addition of antigen. The findings, in total, indicated that a combination of FcepsilonRI and Kit-mediated signals and transcriptional processes were required for optimal physiologic responses of human mast cells to antigen.

Calcium↗