Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.

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Role of STAT3 in Cancer Metastasis and Translational Advances

BioMed Research International ◽

10.1155/2013/421821 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 149

Author(s):

Mohammad Zahid Kamran ◽

Prachi Patil ◽

Rajiv P. Gude

Keyword(s):

Cancer Metastasis ◽

Cellular Proliferation ◽

Nuclear Translocation ◽

Signal Transducer ◽

Surface Receptors ◽

Physiological Conditions ◽

Stat3 Signaling ◽

Tumor Growth And Metastasis ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.

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Dysregulation of protein kinase C in adult depression and suicide: evidence from postmortem brain studies

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyab003 ◽

2021 ◽

Author(s):

Ghanshyam N Pandey ◽

Anuradha Sharma ◽

Hooriyah S Rizavi ◽

Xinguo Ren

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Protein Expression ◽

Mrna Expression ◽

Postmortem Brain ◽

Cortical Region ◽

Cytosol Fraction ◽

Kinase C ◽

Pkc Isozymes

Abstract Background Several lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study we examined the role of PKC isozymes in depression and suicide. Methods We determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region [Brodmann area 9 (BA9)] in 24 normal control (NC) subjects, 24 depressed suicide (DS) subjects and 12 depressed non-suicide (DNS) subjects. The levels of mRNA in the prefrontal cortex (PFC) were determined by qRT-PCR and the protein expression was determined by Western blotting. Results We observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ and PKCε and decreased protein expression either in the membrane or the cytosol fraction of PKC isozymes - PKCα, PKCβI, PKCβII and PKCδ in DS and DNS subjects compared with NC subjects. Conclusions The current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.

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The Role of Signal Transducer and Activator of Transcription 3 (Stat3) in Stretch Injury to Bladder Smooth Muscle Cells

Journal of Pediatric Urology ◽

10.1016/j.jpurol.2007.01.047 ◽

2007 ◽

Vol 3 ◽

pp. S35

Author(s):

Sarel Halachmi ◽

Karen Aitken ◽

Martha Szybowska ◽

Nesrin Sabha ◽

Shariff Dessouki ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Signal Transducer ◽

Bladder Smooth Muscle ◽

Stretch Injury ◽

Transcription 3

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Uterine epithelial LIF receptors contribute to implantation chamber formation in blastocyst attachment

Endocrinology ◽

10.1210/endocr/bqab169 ◽

2021 ◽

Author(s):

Yamato Fukui ◽

Yasushi Hirota ◽

Tomoko Saito-Fujita ◽

Shizu Aikawa ◽

Takehiro Hiraoka ◽

...

Keyword(s):

Hormone Receptor ◽

Leukemia Inhibitory Factor ◽

Ovarian Hormones ◽

Signal Transducer ◽

Blastocyst Implantation ◽

Implantation Process ◽

Uterine Glands ◽

Transcription 3

Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

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Regulation of arginine vasopressin mRNA in rat fetal hypothalamic cell culture. Role of protein kinases and glucocorticoids

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0100051 ◽

1993 ◽

Vol 10 (1) ◽

pp. 51-57 ◽

Cited By ~ 8

Author(s):

S-B Hu ◽

L A Tannahill ◽

S L Lightman

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Mrna Expression ◽

Protein Kinase A ◽

Arginine Vasopressin ◽

In Situ Hybridization Histochemistry ◽

Kinase C ◽

Kinase A

ABSTRACT Studies have been performed to investigate the regulation of arginine vasopressin (AVP) mRNA expression in fetal hypothalamic cultures. AVP mRNA-positive neurones were identified by in-situ hybridization histochemistry, and changes in mRNA expression were quantitated by nuclease protection assay. Both protein kinase C and protein kinase A activators increased the expression of AVP mRNA, in contrast to dexamethasone, which inhibited the responses to both protein kinase C and protein kinase A activation.

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The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

Cancers ◽

10.3390/cancers10090327 ◽

2018 ◽

Vol 10 (9) ◽

pp. 327 ◽

Cited By ~ 39

Author(s):

Loukik Arora ◽

Alan Kumar ◽

Frank Arfuso ◽

Wee Chng ◽

Gautam Sethi

Keyword(s):

Hematological Malignancies ◽

Signal Transducer ◽

Therapeutic Approaches ◽

Janus Kinases ◽

Constitutive Activation ◽

Targeted Inhibition ◽

Transcription Activators ◽

Apoptotic Effects ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

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Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3)

Human Reproduction Update ◽

10.1093/humupd/dmn010 ◽

2008 ◽

Vol 14 (4) ◽

pp. 335-344 ◽

Cited By ~ 106

Author(s):

J. S. Fitzgerald ◽

T. G. Poehlmann ◽

E. Schleussner ◽

U. R. Markert

Keyword(s):

Trophoblast Invasion ◽

Intracellular Cytokine ◽

Signal Transducer ◽

Transcription 3

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The role of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral nerve sheath tumours

Histopathology ◽

10.1111/his.13154 ◽

2017 ◽

Vol 70 (6) ◽

pp. 946-953 ◽

Cited By ~ 5

Author(s):

Gauri Panse ◽

Cheuk H Leung ◽

Davis R Ingram ◽

Khalida Wani ◽

Keila E Torres ◽

...

Keyword(s):

Peripheral Nerve ◽

Signal Transducer ◽

Nerve Sheath ◽

Transcription 3

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Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells

Biochemical Journal ◽

10.1042/bj20110302 ◽

2011 ◽

Vol 441 (1) ◽

pp. 407-416 ◽

Cited By ~ 8

Author(s):

Sung Nyo Yoon ◽

Kang Sik Kim ◽

Ju Hwan Cho ◽

Weina Ma ◽

Hye-Jin Choi ◽

...

Keyword(s):

Neurite Outgrowth ◽

Dominant Negative ◽

Signal Transducer ◽

Downstream Effector ◽

Phospholipase D1 ◽

Protein Kinase Cα ◽

Phosphoinositide 3 Kinase ◽

Interfering Rna ◽

Transcription 3

The purpose of the present study was to investigate the role of PLD (phospholipase D) in bFGF (basic fibroblast growth factor)-induced Bcl-2 expression and to examine whether overexpressed Bcl-2 influences neurite outgrowth in immortalized hippocampal progenitor cells (H19-7 cells). We found that Bcl-2 expression was maximally induced by bFGF within 24 h, and that this effect was reduced by inhibiting PLD1 expression with PLD1 small interfering RNA or by overexpressing DN (dominant-negative)-PLD1, whereas PLD1 overexpression markedly induced Bcl-2 expression. bFGF treatment activated Ras, Src, PI3K (phosphoinositide 3-kinase), PLCγ (phospholipase Cγ) and PKCα (protein kinase Cα). Among these molecules, Src and PKCα were not required for Bcl-2 expression. PLD activity was decreased by Ras, PI3K or PLCγ inhibitor, suggesting that PLD1 activation occurred through Ras, PI3K or PLCγ. We found that Ras was the most upstream molecule among these proteins, followed by the PI3K/PLCγ pathway, indicating that bFGF-induced PLD activation took place through the Ras/PI3K/PLCγ pathway. Furthermore, PLD1 was required for activation of JNK (c-Jun N-terminal kinase), which led to activation of STAT3 (signal transducer and activator of transcription 3) and finally Bcl-2 expression. When Bcl-2 was overexpressed, neurite outgrowth was stimulated along with induction of neurotrophic factors such as brain-derived neurotrophic factor and neurotrophin 4/5. In conclusion, PLD1 acts as a downstream effector of bFGF/Ras/PI3K/PLCγ signalling and regulates Bcl-2 expression through JNK/STAT3, which leads to neurite outgrowth in H19-7 cells.

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