RESUMO
Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggesting that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. To address this question, we conducted a comparative analysis of the transcriptomic profiles of human monocyte-derived macrophages (MDMs) exposed to IL-27 and those exposed to recombinant human IFN-α, IFN-γ, and IFN-λ. We utilized bioinformatics approaches to identify common differentially expressed genes between the different transcriptomes. To verify the accuracy of this approach, we used RT-qPCR, ELISA, flow cytometry, and microarrays data. We found that IFNs and IL-27 induce transcriptional changes in several genes, including those involved in JAK-STAT signaling, and induce shared pro-inflammatory and antiviral pathways in MDMs, leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs)Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response. Given this similarity, we propose that IL-27 could be classified as a distinct type of IFN, possibly categorized as IFN-pi (IFN-π), the type V IFN (IFN-V).
Assuntos
Febre de Chikungunya , Dengue , Interleucina-27 , Janus Quinases , Macrófagos , Transdução de Sinais , Humanos , Células Cultivadas , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/fisiologia , Vírus da Dengue/imunologia , Interferons/metabolismo , Interleucina-27/metabolismo , Interleucinas/imunologia , Interleucinas/farmacologia , Janus Quinases/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Transdução de Sinais/genética , Fatores de Transcrição STAT/metabolismo , Transcriptoma , Replicação ViralRESUMO
Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression.
Assuntos
Neoplasias da Mama , Transdução de Sinais , Humanos , Feminino , Transdução de Sinais/fisiologia , Janus Quinases/metabolismo , Prolactina/metabolismo , Interleucina-6/metabolismo , Fatores de Transcrição STAT/metabolismoRESUMO
The Krüppel-like factor 13 (KLF13) has emerged as an important transcription factor involved in essential processes of the central nervous system (CNS). It predominantly functions as a transcriptional repressor, impacting the activity of several signaling pathways with essential roles in the CNS, including the JAK/STAT pathway, which is the canonical mediator of growth hormone (GH) signaling. It is now recognized that GH has important actions as a neurotrophic factor. Therefore, we analyzed the effects of KLF13 on the activity of the JAK/STAT signaling pathway in the hippocampus-derived cell line HT22. Results showed that KLF13 directly regulates the expression of several genes involved in the JAK-STAT pathway, including Jak1, Jak2, Jak3, and Socs1, by associating with their proximal gene promoters. In addition, it was found that in KLF13-deficient HT22 neurons, the expression of Jak1, Stat3, Socs1, Socs3, and Igf1 was dysregulated, exhibiting mRNA levels that went up to 7-fold higher than the control cell line. KLF13 displayed a differential effect on the GH-induced JAK/STAT pathway activity, decreasing the STAT3 branch while enhancing the STAT5 branch. In KLF13-deficient HT22 cells, the activity of the STAT3 branch was enhanced, mediating the GH-dependent augmented expression of the JAK/STAT output genes Socs1, Socs3, Igf1, and Bdnf. Furthermore, GH treatment increased both the nuclear content of KLF13 and Klf13 mRNA levels, suggesting that KLF13 could be part of the mechanisms that maintain the homeostatic state of this pathway. These findings support the notion that KLF13 is a regulator of JAK/STAT activity.
Assuntos
Janus Quinases , Transdução de Sinais , Janus Quinases/genética , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , RNA Mensageiro/metabolismoRESUMO
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.
Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Transdução de Sinais/fisiologia , Neoplasias do Colo do Útero/genética , Infecções por Papillomavirus/genética , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismoRESUMO
Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.
Assuntos
Janus Quinases , Fatores de Transcrição STAT , Humanos , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/fisiologia , Citocinas/metabolismo , Inflamação/tratamento farmacológicoRESUMO
The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different JAK-STAT signaling patterns have potential indications for various medical conditions. The main dermatological targets of JAK-STAT pathway inhibitors are inflammatory or autoimmune diseases such as psoriasis, vitiligo, atopic dermatitis and alopecia areata; however, several dermatoses are under investigation to expand this list of indications. As JAK-STAT pathway inhibitors should gradually occupy a relevant space in dermatological prescriptions, this review presents the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to validate the best dermatological practice.
Assuntos
Dermatologia , Inibidores de Janus Quinases , Vitiligo , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Vitiligo/tratamento farmacológicoRESUMO
PURPOSE: To investigate the role of cyanidin-3-O-glucoside (C3G) in renal ischemia/reperfusion (I/R) injury and the potential mechanisms. METHODS: Mouse models were established by clamping the left renal vessels, and in vitro cellular models were established by hypoxic reoxygenation. RESULTS: Renal dysfunction and tissue structural damage were significantly higher in the I/R group. After treatment with different concentrations of C3G, the levels of renal dysfunction and tissue structural damage decreased at different levels. And its protective effect was most pronounced at 200 mg/kg. The use of C3G reduced apoptosis as well as the expression of endoplasmic reticulum stress (ERS)-related proteins. Hypoxia/reoxygenation (H/R)-induced apoptosis and ERS are dependent on oxidative stress in vitro. In addition, both AG490 and C3G inhibited the activation of JAK/STAT pathway and attenuated oxidative stress, ischemia-induced apoptosis and ERS. CONCLUSIONS: The results demonstrated that C3G blocked renal apoptosis and ERS protein expression by preventing reactive oxygen species (ROS) production after I/R via the JAK/STAT pathway, suggesting that C3G may be a potential therapeutic agent for renal I/R injury.
Assuntos
Nefropatias , Traumatismo por Reperfusão , Camundongos , Animais , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Fatores de Transcrição STAT/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Apoptose , Isquemia , Glucosídeos/farmacologiaRESUMO
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that affects the central nervous system (CNS), varying from relatively benign to severely disabling. Although the roles of several cytokines and chemokines in MS are well established, their roles in MS lesions and evolution remain a matter of debate. Soluble CD40L (sCD40L) is a ligand that induces lymphocyte proinflammatory activity by stimulating the activation and maturation of B cells, promoting isotype switching and affinity hypermutation. Circulating sCD40L levels reflect activation of the CD40-CD40L complex. The interaction between CD40 and CD40L is of fundamental importance, suggesting their role in MS pathogenesis. Interleukin-31 (IL-31) is a proinflammatory cytokine that plays a role in allergies, autoimmune diseases, and is a major factor in several chronic inflammatory diseases. IL-31 triggers the JAK-STAT pathway in several different cell types, to induce proliferation and tissue remodeling in fibroblasts, epithelial cells, and endothelial cells. Some studies have described a correlation between these two cytokines and decreased serum levels of sCD40L and IL-31 after MS treatment, accompanied by a lower inflammatory response. In this review, we emphasize the possible correlation and positive feedback between IL31 and sCD40L in the MS proinflammatory response. We also describe the justification for this hypothesis and whether it is possible to investigate these cytokines as biomarkers of MS.
Assuntos
Ligante de CD40 , Esclerose Múltipla , Humanos , Ligante de CD40/metabolismo , Células Endoteliais/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Biomarcadores , Interleucinas , CitocinasRESUMO
OBJECTIVES: TTP488, an antagonist of the receptor for advanced glycation end-products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). However, the mechanism underlying the protective action of TTP488 against AD has not yet been fully explored. METHODS: Healthy male rats were exposed to aberrant amyloid ß (Aß) 1-42. Lipopolysaccharide (LPS) and the NOD-like receptor family pyrin domain containing 1 (NLRP1) overexpression lentivirus were injected to activate the NLRP1 inflammasome and exacerbate AD. TTP488 was administered to reverse AD injury. Finally, tofacitinib and fludarabine were used to inhibit the activity of Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) to prove the relationship between the JAK/STAT signaling pathway and TTP488. RESULTS: LPS and NLRP1 overexpression significantly increased the NLRP1 levels, reduced neurological function, and aggravated neuronal damage, as demonstrated by the impact latency time of, time spent by, and length of the platform covered by, the mice in the Morris water maze assay, Nissl staining, and immunofluorescence staining in rats with AD. CONCLUSIONS: TTP488 administration successfully reduced AD injury and reversed the aforementioned processes. Additionally, tofacitinib and fludarabine administration could further reverse AD injury after the TTP488 intervention. These results suggest a new potential mechanism underlying the TTP488-mediated alleviation of AD injury.
Assuntos
Doença de Alzheimer , Imidazóis , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Imidazóis/farmacologia , Janus Quinase 2 , Janus Quinases/metabolismo , Masculino , Camundongos , Ratos , Receptor para Produtos Finais de Glicação Avançada , Fatores de Transcrição STAT/metabolismo , TirosinaRESUMO
OBJECTIVE: Altered homeostasis of salivary gland (SG) epithelial cells in Sjögren's syndrome (SS) could be the initiating factor that leads to inflammation, secretory dysfunction and autoimmunity. Autophagy is an important homeostatic mechanism, whose deficiency is associated with inflammation and accumulation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) components. We aimed to evaluate whether autophagy is altered in labial SG (LSG) epithelial cells from primary SS (pSS) patients and whether this contributes to inflammation through the JAK-STAT pathway. Furthermore, we investigated the anti-inflammatory effect of the JAK inhibitor tofacitinib in autophagy-deficient (ATG5 knockdown) three-dimensional (3D)-acini. METHODS: We analysed LSG biopsies from 12 pSS patients with low focus score and 10 controls. ATG5-deficient 3D-acini were generated and incubated with IL-6 in the presence or absence of tofacitinib. Autophagy markers, pro-inflammatory cytokine expression, and JAK-STAT pathway activation were evaluated by PCR or western blot, along with correlation analyses between the evaluated markers and clinical parameters. RESULTS: LSG from pSS patients showed increased p62 and decreased ATG5 expression, correlating negatively with increased activation of JAK-STAT pathway components (pSTAT1 and pSTAT3). Increased expression of STAT1 and IL-6 correlated with EULAR Sjögren's syndrome disease activity index and the presence of anti-Ro antibodies. ATG5-deficient 3D-acini reproduced the findings observed in LSG from pSS patients, showing increased expression of pro-inflammatory markers such as IL-6, which was reversed by tofacitinib. CONCLUSION: Decreased expression of ATG5 in LSG epithelial cells from pSS patients possibly contributes to increased inflammation associated with JAK-STAT pathway activation, as evidenced in ATG5-deficient 3D-acini. Interestingly, these results suggest that tofacitinib could be used as an anti-inflammatory agent in pSS patients.