Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells.

Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.

STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges.

Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.

Prevention of Renal Interstitial Fibrosis by Suplatast in a Mouse Model.

Suplatast is a T helper 2 (Th2) cytokine inhibitor. Here, we tested its therapeutic effects using a mouse model of renal interstitial fibrosis caused by unilateral ureteral obstruction (UUO). In this model, suplatast was found to prevent the induced fibrosis in the obstructed kidney when given in the drinking water at 100 mg/kg/d. Mechanistically, suplaplast inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) that was otherwise increased by UUO. Similarly, suplaplast reduced the increased accumulation of KIM-1, transforming growth factor ß (TGF-ß), type I collagen, interleukin-4 (IL-4), janus kinase (JAK)1 and signal transducer and activator of transcription (STAT)3 mRNA seen in the kidneys of UUO-treated mice. Furthermore, STAT3 phosphorylation, which was stimulated by UUO, was also significantly decreased by suplatast. Collectively, these data show that suplatast reduces UUO-induced renal interstitial fibrosis via mechanisms including a reduction of phosphorylation of ERK and JAK/STAT pathway signaling.

Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples.

It is theorized that dysregulated immune responses to infectious insults contribute to the development of pediatric B-ALL. In this context, our understanding of the immunomodulatory-mediator-induced signaling responses of leukemic blasts in pediatric B-ALL diagnostic samples is rather limited. Hence, in this study, we defined the signaling landscape of leukemic blasts, as well as normal mature B cells and T cells residing in diagnostic samples from 63 pediatric B-ALL patients. These samples were interrogated with a range of immunomodulatory-mediators within 24 h of collection, and phosflow analyses of downstream proximal signaling nodes were performed. Our data reveal evidence of basal hyperphosphorylation across a broad swath of these signaling nodes in leukemic blasts in contrast to normal mature B cells and T cells in the same sample. We also detected similarities in the phosphoprotein signature between blasts and mature B cells in response to IFNγ and IL-2 treatment, but significant divergence in the phosphoprotein signature was observed between blasts and mature B cells in response to IL-4, IL-7, IL-10, IL-21 and CD40 ligand treatment. Our results demonstrate the existence of both symmetry and asymmetry in the phosphoprotein signature between leukemic and non-leukemic cells in pediatric B-ALL diagnostic samples.

Profound differences in IgE and IgG recognition of micro-arrayed allergens in hyper-IgE syndromes.

BACKGROUND: The specificities of IgE and IgG for allergen molecules in patients with inborn errors of immunity (IEI) have not been investigated in detail. OBJECTIVE: To study IgE and IgG antibody specificities in patients with defined hyper-IgE syndromes (HIES) using a comprehensive panel of allergen molecules. METHODS: We used chips containing micro-arrayed allergen molecules to analyze allergen-specific IgE and IgG levels in sera from two groups of HIES patients: Autosomal recessive mutations in phosphoglucomutase-3 (PGM3); Autosomal dominant negative mutations of STAT3 (STAT3); and age-matched subjects with allergic sensitizations. Assays with rat basophil leukemia cells transfected with human FcεRI were performed to study the biological relevance of IgE sensitizations. RESULTS: Median total IgE levels were significantly lower in the sensitized control group (212.9 kU/L) as compared to PGM3 (5042 kU/L) and STAT3 patients (2561 kU/L). However, PGM3 patients had significantly higher allergen-specific IgE levels and were sensitized to a larger number of allergen molecules as compared to STAT3 patients. Biological relevance of IgE sensitization was confirmed for PGM3 patients by basophil activation testing. PGM3 patients showed significantly lower cumulative allergen-specific IgG responses in particular to milk and egg allergens as compared to STAT3 patients and sensitized controls whereas total IgG levels were comparable to STAT3 patients and significantly higher than in controls. CONCLUSION: The analysis with multiple micro-arrayed allergen molecules reveals profound differences of allergen-specific IgE and IgG recognition in PGM3 and STAT3 patients which may be useful for classification of IEI and clinical characterization of patients.

The potential and controversy of targeting STAT family members in cancer.

The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play a complex and essential role in the regulation of physiologic cell processes, such as proliferation, differentiation, apoptosis and angiogenesis, and serves to organize the epigenetic landscape of immune cells. To date, seven STAT genes have been identified in the human genome; STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. They all account for diverse effects in response to extracellular signaling proteins, mainly by altering gene transcription in the effector cells. Members of the STAT family have been implicated in human cancer development, progression, metastasis, survival and resistance to treatment. Particularly STAT3 and STAT5 are of interest in cancer biology. They are currently considered as oncogenes, but their signaling is embedded into a complex and delicate balance between different (counteracting) transcription factors, and thus, in some contexts they can have a tumor suppressive role. Assessing STAT signaling mutations as well as screening for aberrant STAT pathway activation may have a role to predict sensitivity to immunotherapy and targeted STAT inhibition. In the present comprehensive review of the literature, we discuss in-depth the role of each STAT family member in cancer, assemble cutting-edge information on the use of these molecules as potential biomarkers and targets for treatment, and address why their clinical implementation is controversy.

Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms.

Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor ß1 (TGF-ß1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.

Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn's disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK-STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK-STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK-STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.

Dendrobium nobile Alkaloids Protects against H2O2-Induced Neuronal Injury by Suppressing JAK-STATs Pathway Activation in N2A Cells.

The purpose of this study was to investigate the preventive effect and mechanism of Dendrobium alkaloids (DNLA) on oxidative stress-related death in neuronal cells. Our results demonstrated that DNLA has a direct neuroprotective effect through oxidative stress in N2A cells induced by hydrogen peroxide (H2O2). CCK8, lactate dehydrogenase (LDH), intracellular Ca2+, intracellular reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were used to evaluate the mechanism of DNLA neutralization by H2O2-induced injury. Results presented in the paper indicate that treatment with DNLA (35 ng/mL) significantly attenuated decreases in cell viability, release of LDH, and apoptosis after H2O2-induced neuronal injury. Furthermore, DNLA significantly reduced intracellular Ca2+ up-regulation, ROS production, and inhibited mitochondrial depolarization. Moreover, DNLA treatment significantly downregulated expressions of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, nitric oxide synthase, janus kinase-signal transducer and activators of transcription (JAK-STATs) signaling in N2A cells, all of which were H2O2-induced. Taken together, our findings suggested that DNLA may inhibit the expression of pro-inflammatory and pro-apoptotic factors by blocking JAK-STATs signaling after oxidative stress injury. This research provides a potential experimental basis for further application of DNLA to prevent various human nervous system diseases caused by oxidative stress.

MicroRNA-125b exerts antitumor functions in cutaneous squamous cell carcinoma by targeting the STAT3 pathway.

BACKGROUND: MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC). However, its function in CSCC has yet to be extensively explored. Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC. METHODS: Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b-STAT3 axis in human CSCC tissues and cell lines. The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay. The MTT assay and flow cytometry were used to determine the role of the miR-125b-STAT3 axis in CSCC cell proliferation and apoptosis. RESULTS: MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues. STAT3 was identified as the direct target of miR-125b. Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis. Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125-STAT3 axis. CONCLUSIONS: Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway. This observation increases our understanding of the molecular mechanisms of CSCC. Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.

AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK/STAT/SOCS pathway.

Cisplatin causes acute kidney injury (AKI) through proximal tubular injury. We investigated the protective effect of the adenosine monophosphate protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) against cisplatin-induced AKI. We investigated whether the AMP-kinase activator AICAR ameliorates cisplatin-induced AKI through the JAK/STAT/SOCS pathway. Male Sprague-Dawley (SD) rats were randomly divided into four groups: control, AICAR, cisplatin, and cisplatin + AICAR. As appropriate to their treatment group, the rats were injected with a single dose of cisplatin (7 mg/kg, i.p.). AICAR was administered to the rats at 100 mg/kg i.p. daily. Blood urea nitrogen (BUN) and serum creatinine were measured. Renal damage was analyzed in sections stained with hematoxylin and eosin (H&E). Renal tissues were also examined by immunohistochemistry and western blot for p-AMPK, Kim-1, cleaved caspase 3, and JAK/STAT/SOCS. For in vitro studies, NRK-52E normal rat kidney cells were treated with cisplatin and/or AICAR. By western blot, we confirmed the expression of p-AMPK and the JAK/STAT/SOCS pathway in NRK-52E cells. AICAR was protective against cisplatin-induced acute tubular injury by up-regulating p-AMPK expression in NRK-52E cells. Protein expression levels of JAK2/STAT1 were markedly ameliorated in NRK-52E cells by AICAR. The protective mechanism of AICAR may be associated with suppression of the JAK2/STAT1 pathway and up-regulation of SOCS1, an inhibitor of the JAK2/STAT1 pathway. The present study demonstrates the protective effects of AICAR against cisplatin-induced AKI and shows a new renoprotective mechanism through the JAK2/STAT1/SOCS1 pathway and apoptosis inhibition. This study suggests that activation of the AMPK activator AICAR might ameliorate cisplatin-induced AKI.

Chylous ascites, anti-interferon-gamma autoantibody, and angioimmunoblastic T-cell lymphoma: a rare but intriguing connection over Mycobacterium avium.

We report a case of non-AIDS (acquired immunodeficiency syndrome), non-CAPD (Continuous Ambulatory Peritoneal Dialysis), non-cirrhotic, Mycobacterium avium peritonitis, which is a rare form of mycobacterial infection. A 66-year-old Japanese man who had been treated previously for angioimmunoblastic T-cell lymphoma (AITL), had developed disseminated M. avium infection. Antimycobacterial regimen improved his symptoms; however, following an interruption in treatment, he developed chylous ascites. The patient died of uncontrolled peritonitis despite intensive treatment. Anti-interferon-γ autoantibody was positive, and AITL was presumed to be involved in autoantibody production. A rare coexistence of chylous ascites, autoantibody, and AITL taught us an intriguing lesson on the pathogenesis of M. avium infection. Particularly, we conclude that treatment strategies for M. avium infection should aim to restore immunity.

JAK/STAT pathway modulation: Does it work in dermatology?

Janus kinase-signal transducer and activator of transcription (JAK/STAT)-is an intracellular signaling pathway, which plays a key role in downstream transmission of extracellular signals from cell membrane to the cell nucleus. This pathway is activated by cytokines, which participate in inflammation, innate and acquired immune responses, and also cell growth. Recent studies point out possible disturbances in JAK/STAT pathway in various inflammatory and autoimmune skin diseases, such as atopic dermatitis, psoriasis, alopecia areata. Several molecules that modulate-inhibit-this pathway are currently under investigation for the evaluation of their clinical use in dermatological diseases. A brief overview of the therapeutical use of JAK/STAT inhibitors in dermatology will be provided here.

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. METHODS: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. RESULTS: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. CONCLUSION: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH.

N-Arylsulfonylsubstituted-1H indole derivatives as small molecule dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and tubulin.

Signal transducer and activator of transcription (STAT3) is a proposed therapeutic target for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 µM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization. This study describes a series of N-arylsulfonylsubstituted-1H indole derivatives as potent anti-cancer agents targeting both STAT3 and tubulin.

Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis.

Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling to transcriptional regulation of target genes, which are involved in cell differentiation, migration, and proliferation. Jak/STAT signaling is involved in various types of blood cell disorders and cancers in humans, and its activation is associated with carcinomas that are more invasive or likely to become metastatic. Despite immense information regarding Jak/STAT regulation, the signaling network has numerous missing links, which is slowing the progress towards developing drug therapies. In mammals, many components act in this cascade, with substantial cross-talk with other signaling pathways. In Drosophila, there are fewer pathway components, which has enabled significant discoveries regarding well-conserved regulatory mechanisms. Work across species illustrates the relevance of these regulators in humans. In this review, we showcase fundamental Jak/STAT regulation mechanisms in blood cells, stem cells, and cell motility. We examine the functional relevance of key conserved regulators from Drosophila to human cancer stem cells and metastasis. Finally, we spotlight less characterized regulators of Drosophila Jak/STAT signaling, which stand as promising candidates to be investigated in cancer biology. These comparisons illustrate the value of using Drosophila as a model for uncovering the roles of Jak/STAT signaling and the molecular means by which the pathway is controlled.

Rituximab Restores IFN-γ-STAT1 Function and Ameliorates Disseminated Mycobacterium avium Infection in a Patient with Anti-Interferon-γ Autoantibody.

A 67-year-old Japanese female with back pain and severe cachexia visited our hospital. The diagnosis was disseminated Mycobacterium avium complex infection (dMAC) with multiple bone involvement. Anti-mycobacterial chemotherapy was started, but fever persisted and dislocation of cervical vertebrae has made her bedridden. Because anti-interferon (IFN)-γ autoantibody was positive, four doses of rituximab 375 mg/m2, every 7 day, were administered. Soon after treatment, progression of osteolytic lesions and wasting has stopped. We proved that rituximab has recovered IFN-γ signaling as shown by IFN-γ-induced STAT1 phosphorylation. It can be a promising option for dMAC cases with anti-IFN-γ autoantibody.

Effect of memory CD4+ T cells' signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma.

BACKGROUND: Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown. METHODS: Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood, and cell surface staining (CD4, CD45RO, CRTH2, CD62L, and CCR7) was performed for the detection of memory CD4+ T cells in blood. After stimulation with interleukin-27 (IL-27) or IL-4 for 15 min, the STAT1/STAT6 phosphorylation of memory CD4+ T cells was measured separately by flow cytometric techniques. The cytokine-releasing profiles after 6 days of culture under neutralization, TH2, TH2 + lipopolysaccharide (LPS), and TH2 + house dust mite (HDM) conditions were detected by intracellular protein (IL-5, IL-17, and interferon (IFN)-γ) staining. Correlation analyses between the profile of memory CD4+ T cells and clinical characteristics of asthma were performed. RESULTS: The number of circulating memory CD4+ T (CD4+ Tm) cells in asthmatics was increased compared with that in the healthy subjects (48 ± 5.7 % vs. 32 ± 4.1 %, p < 0.05). Compared with COPD and healthy subjects, the phosphorylation of signal transducer and activator of transcription 1 (STAT1-py) was impaired in asthmatics, whereas the phosphorylation of signal transducer and activator of transcription 6 (STAT6-py) was slightly enhanced. This imbalance of STAT1-py/STAT6-py was attributed to TH2 memory cells but not non-TH2 memory cells in blood. The cytokine-releasing profiles of asthmatics was unique, specifically IL-5high, IL-17high, and IFN-rlow, compared with those of COPD patients and healthy subjects. The IL-17 production levels in CD4+ Tm cells are associated with disease severity and positively correlated with medication consumption in asthma. CONCLUSIONS: The long-lived, antigen-specific memory CD4+ T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma. Memory CD4+ T cells exhibiting a shift in STAT phosphorylation and specific cytokine-releasing profiles have the potential to facilitate the understanding of disease heterogeneity and severity, allowing the more personalized treatment of patients.

Inhibitory effects of propofol on Th17 cell differentiation.

Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous anesthetic agent in daily practice. It has been reported to show immunomodulatory activity. However, the effect of propofol on the differention of T cells remains unclear. In this study, we demonstrated for the first time that propofol inhibited both interleukin (IL)-6 plus transforming growth factor-ß (TGF-ß)-induced Th17 cell differentiation in vitro and in LPS-challenged mice. Propofol also suppressed the IL-6-induced phosphorylation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription (STAT3) pathway, a cytokine-activated essential transcription factor in Th17 cell development, which occurred concomitantly with the enhancement of suppressor of cytokine signaling-3 (SOCS3) expression involved in the downregulation of STAT3 phosphorylation. These data extend our knowledge of the immunosuppressive effects of propofol and their underlying mechanism.

Oncostatin M-dependent Mcl-1 induction mediated by JAK1/2-STAT1/3 and CREB contributes to bioenergetic improvements and protective effects against mitochondrial dysfunction in cortical neurons.

Oncostatin M (OSM), a cytokine in the interleukin-6 (IL-6) family, has been proposed to play a protective role in the central nervous system, such as attenuation of excitotoxicity induced by N-methyl-D-aspartate (NMDA) and glutamate. However, the potential neuroprotective effects of OSM against mitochondrial dysfunction have never been reported. In the present study, we tested the hypothesis that OSM may confer neuronal resistance against 3-nitropropionic acid (3-NP), a plant toxin that irreversibly inhibits the complex II of the mitochondrial electron transport chain, and characterized the underlying molecular mechanisms. We found that OSM preconditioning dose- and time-dependently protected cortical neurons against 3-NP toxicity. OSM stimulated expression of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 family member expressed in differentiating myeloid cells, that required prior phosphorylation of Janus kinase-1 (JAK1), JAK2, extracellular signal-regulated kinase-1/2 (ERK1/2), signal transducer and activator of transcription-3 (STAT3), STAT1, and cAMP-response element-binding protein (CREB). Pharmacological inhibitors of JAK1, JAK2, ERK1/2, STAT3, STAT1, and CREB as well as the siRNA targeting at STAT3 and Mcl-1 all abolished OSM-dependent 3-NP resistance. Finally, OSM-dependent Mcl-1 induction contributed to the enhancements of mitochondrial bioenergetics including increases in spare respiratory capacity and ATP production. In conclusion, our findings indicated that OSM induces Mcl-1 expression via activation of ERK1/2, JAK1/2, STAT1/3, and CREB; furthermore, OSM-mediated Mcl-1 induction contributes to bioenergetic improvements and neuroprotective effects against 3-NP toxicity in cortical neurons. OSM may thus serve as a novel neuroprotective agent against mitochondrial dysfunction commonly associated with pathogenic mechanisms underlying neurodegeneration.