Janus Kinase-signal Transducer And Activator Of Transcription Signaling Research Articles

Multi-omics analysis uncovered systemic lupus erythematosus and COVID-19 crosstalk

BackgroundStudies have highlighted a possible crosstalk between the pathogeneses of COVID-19 and systemic lupus erythematosus (SLE); however, the interactive mechanisms remain unclear. We aimed to elucidate the impact of COVID-19 on SLE using clinical information and the underlying mechanisms of both diseases.MethodsRNA-seq datasets were used to identify shared hub gene signatures between COVID-19 and SLE, while genome-wide association study datasets were used to delineate the interaction mechanisms of the key signaling pathways. Finally, single-cell RNA-seq datasets were used to determine the primary target cells expressing the shared hub genes and key signaling pathways.ResultsCOVID-19 may affect patients with SLE through hematologic involvement and exacerbated inflammatory responses. We identified 14 shared hub genes between COVID-19 and SLE that were significantly associated with interferon (IFN)-I/II. We also screened and obtained four core transcription factors related to these hub genes, confirming the regulatory role of the IFN-I/II-mediated Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway on these hub genes. Further, SLE and COVID-19 can interact via IFN-I/II and IFN-I/II receptors, promoting the levels of monokines, including interleukin (IL)-6/10, tumor necrosis factor-α, and IFN-γ, and elevating the incidence rate and risk of cytokine release syndrome. Therefore, in SLE and COVID-19, both hub genes and core TFs are enriched within monocytes/macrophages.ConclusionsThe interaction between SLE and COVID-19 promotes the activation of the IFN-I/II-triggered JAK-STAT signaling pathway in monocytes/macrophages. These findings provide a new direction and rationale for diagnosing and treating patients with SLE–COVID-19 comorbidity.

Hsa_circ_0004214 involved in the epithelial-mesenchymal transition induced by beryllium sulfate through modulating JAK-STAT signaling pathway.

Chronic beryllium disease is characterized by granulomas and pulmonary fibrosis. Recent studies have shown that microRNAs (miRNAs) and circular RNAs (circRNAs) play critical roles in the pathogenesis and development of many diseases. However, the role of miRNAs and circRNAs in pulmonary fibrosis induced by beryllium sulfate (BeSO4) has not been elucidated. Previous studies demonstrated hsa-miR-663b was down-regulated in the 150 μmol/L BeSO4-treated 16HBE cells, while hsa_circ_ 0004214 was up-regulated. Here we found epithelial-mesenchymal transition (EMT) involved in pulmonary fibrosis induced by BeSO4 (4, 8, and 12 mg/kg·BW) in SD rats. Elevated expression of hsa-miR-663b blocked the EMT progression of 16HBE cells induced by 150 μmol/L BeSO4. Notably, the overexpression of hsa-miR-663b decreased the expression of leukemia inhibitory factor (LIF), which was predicted as a target gene of hsa-miR-663b by bioinformatics tools. Furthermore, elevated miR-663b inhibited the activation of the downstream Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway induced by BeSO4 in 16HBE cells. Previous study suggested that hsa_circ_0004214 had binding sites for hsa-miR-663b. The results indicated hsa_circ_0004214 alleviated the BeSO4-induced EMT via JAK-STAT pathway in 16HBE cells. Collectively, the overexpression of hsa-miR-663b and knockdown of hsa_circ_0004214 attenuated the EMT induced by BeSO4 through the inhibition of JAK-STAT signaling pathway. The aberrant expressed hsa-miR-663b and hsa_circ_0004214 stimulated by BeSO4 may exert an important function in the toxic mechanism of beryllium exposure to 16HBE cells, providing the potential therapeutic targets in chronic beryllium disease.

Evolutionary, comparative, and functional analyses of STATs and regulation of the JAK-STAT pathway in lumpfish upon bacterial and poly(I:C) exposure.

The Janus kinase/signal transducers and activators of transcription (JAK-STAT) system regulates several biological processes by affecting transcription of genes as a response to cytokines and growth factors. In the present study, we have characterized the STAT genes in lumpfish (Cyclopterus lumpus L.), belonging to the order Perciformes, and investigated regulation of the JAK-STAT signaling pathway upon exposure to bacteria (Vibrio anguillarum) and poly(I:C), the latter mimicking antiviral responses. Characterization and evolutionary analyses of the STATs were performed by phylogeny, protein domain, homology similarity and synteny analyses. Antibacterial and antiviral responses were investigated by performing KEGG pathway analysis. We observed that lumpfish have stat1a, 2, 3, 4, 5a, 5b, and 6. Transcriptome-wide analyses showed that most components of the JAK-STAT pathway were present in lumpfish. il-6, il-10, il-21, iκBα and stat3 were upregulated 6 hours post exposure (hpe) against bacteria while type I interferons (IFNs), irf1, irf3, irf10, stat1 and 2 were upregulated 24 hpe against poly(I:C). Our findings shed light on the diversity and evolution of the STATs and the data show that the STAT genes are highly conserved among fish, including lumpfish. The transcriptome-wide analyses lay the groundwork for future research into the functional significance of these genes in regulating critical biological processes and make an important basis for development of prophylactic measure such as vaccination, which is highly needed for lumpfish since it is vulnerable for both bacterial and viral diseases.

Silencing SIRT1 promotes the anti-HBV action of IFN-α by regulating Pol expression and activating the JAK-STAT signaling pathway

PurposeThe purpose this study is to investigate the impact of SIRT1 on the anti-HBV activity of IFN-α and further elucidate its underlying mechanism. MethodsHepG2.2.15 cells stably transfected with HBV virus were chosen as the primary study subject. IFN-α was used to stimulate the cells and regulate the expression of SIRT1, and the JAK-STAT pathway and HBV-related indices were measured by qRT-PCR, Western blotting and ELISA. Immunofluorescence (IF) was used to detect the nuclear translocation of STAT1 and STAT2. Coimmunoprecipitation (Co-IP) was used to detect the binding of SIRT1 to HBV Polymerase (Pol). ResultsIn HepG2.2.15 cells, we found changes in SIRT1 expression. We show that silencing SIRT1 promotes the IFN-α-triggered Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Importantly, SIRT1 can interact with Pol and increase JAK-STAT activity by regulating Pol expression. Additionally, the inhibition of SIRT1 activity by treatment with the SIRT1 inhibitor selisistat enhanced the anti-HBV effect of IFN-α and JAK-STAT pathway activity. ConclusionIn conclusion, our results demonstrate that silencing SIRT1 activates the JAK-STAT pathway and enhances the anti-HBV activity of IFN-α by inhibiting Pol expression. This would be a promising therapeutic target to improve the efficacy of IFN-α in the treatment of CHB.

Identification, expression pattern and functional characterization of IFN-γ involved in activating JAK-STAT pathway in Sebastes schlegeli.

IFN-γ (interferon gamma) is a critical cytokine in the immune system involved both directly and indirectly in antiviral activity, stimulation of bactericidal activity, antigen presentation and activation of macrophages via the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. The IFN-γ function is best described in cell defense against intracellular pathogens in mammals, but IFN-γ cytokine-induced metabolic change and its role in anti-infection remain unknown in teleost fish. In this study, a novel IFN-γ (SsIFN-γ) was identified from black rockfish (Sebastes schlegeli) by rapid amplification of cDNA ends (RACE). The open reading frame (ORF) of SsIFN-γ encoded a putative protein of 215 amino acids and shares 60.2%-93.5% overall sequence identities with other teleost IFN-γ. SsIFN-γ was distributed ubiquitously in all the detected tissues and immune cells, which was highly expressed in the spleen, gills, head kidney by quantitative real-time PCR. The mRNA expression of SsIFN-γ was significantly upregulated in the spleen, head kidney, head kidney (HK) macrophages and peripheral blood lymphocytes (PBLs) during pathogen infection. Meanwhile, the recombinant protein (rSsIFN-γ) exhibited an immunomodulatory function to enhance respiratory burst activity and nitric oxide response of HK macrophages. Furthermore, rSsIFN-γ could effectively upregulate the expression of macrophage proinflammatory cytokine, the expression of JAK-STAT signaling pathway related genes and interferon-related downstream genes in the head kidney and spleen. Luciferase assays showed ISRE and GAS activity were obviously enhanced after rSsIFN-γ treatment. These results indicated that SsIFN-γ possessed apparent immunoregulatory properties and played a role in fighting pathogen infection which will be helpful to further understanding of the immunologic mechanism of teleosts IFN-γ in innate immunity.

Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway

BackgroundAbnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia.MethodsMicroglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups.ResultsThe study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c‑Jun N‑terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3.ConclusionsThe results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms.

Proteomic and phosphoproteomic analysis reveal threonine deficiency increases hepatic lipid deposition in Pekin ducks via reducing STAT phosphorylation.

Dietary threonine (Thr) deficiency enhances triglyceride (TG) deposition in the liver of Pekin ducks, which injures hepatic function and impairs growth performance. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the effects of dietary Thr deficiency on the expressions of proteins and phosphoproteins in liver of Pekin ducks, to identify the underlying molecular changes. A total of 300 one-day-old ducklings were divided into 3 groups with 10 replicates of 10 birds. All ducks were fed corn-wheat-peanut meal diets containing 0.46%, 0.71%, and 0.96% Thr, respectively, from 1 to 21 days of age. Growth performance, serum parameters, hepatic TG content, and expression of genes involved in lipid metabolism of Pekin ducks were determined. A Thr deficiency group (Thr-D, 0.46% Thr) and a Thr sufficiency group (Thr-S, 0.71% Thr) were selected for subsequent proteomic and phosphoproteomic analysis. The results showed that Thr-D reduced the growth performance (P<0.001), and increased the plasma concentrations of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and hepatic TG (P<0.05). Thr-D increased gene expression related to fatty acid and TG synthesis (P<0.05). A total of 176 proteins and 259 phosphosites (containing 198 phosphoproteins) were observed to be differentially expressed as a result of Thr-D. The upregulated proteins were enriched in the pathway related to amino acid metabolism, peroxisome. The downregulated proteins were enriched in linolenic and arachidonic acid metabolism, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The upregulated phosphoproteins were enriched in the pathways related to fatty acid biosynthesis, fructose and mannose metabolism, and glycolysis/gluconeogenesis. Thr-D reduced the phosphorylation of STAT1 at S729 and STAT3 at S728, and expression of STAT5B. In contrast, Thr-D increased non-receptor tyrosine-protein kinase (TYK2) expression and STAT1 phosphorylation at S649. Taken together, dietary Thr-D increased hepatic TG accumulation by upregulating the expression of genes and proteins, and phosphoproteins related to fatty acid and triglyceride synthesis. Furthermore, these processes might be regulated by the JAK-STAT signaling pathway, especially the phosphorylation of STAT1 and STAT3.

JAK-STAT activation contributes to cytotoxic T cell–mediated basal cell death in human chronic lung allograft dysfunction

Chronic lung allograft dysfunction (CLAD) is the leading cause of death in lung transplant recipients. CLAD is characterized clinically by a persistent decline in pulmonary function and histologically by the development of airway-centered fibrosis known as bronchiolitis obliterans. There are no approved therapies to treat CLAD, and the mechanisms underlying its development remain poorly understood. We performed single-cell RNA-Seq and spatial transcriptomic analysis of explanted tissues from human lung recipients with CLAD, and we performed independent validation studies to identify an important role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in airway epithelial cells that contributes to airway-specific alloimmune injury. Specifically, we established that activation of JAK-STAT signaling leads to upregulation of major histocompatibility complex 1 (MHC-I) in airway basal cells, an important airway epithelial progenitor population, which leads to cytotoxic T cell-mediated basal cell death. This study provides mechanistic insight into the cell-to-cell interactions driving airway-centric alloimmune injury in CLAD, suggesting a potentially novel therapeutic strategy for CLAD prevention or treatment.

The Staphylococcus aureus protein IsdA increases SARS CoV-2 replication by modulating JAK-STAT signaling

The Severe Acute Respiratory Syndrome Coronavirus 2 (CoV-2) pandemic has affected millions globally. A significant complication of CoV-2 infection is secondary bacterial co-infection, as seen in approximately 25% of severe cases. The most common organism isolated during co-infection is Staphylococcus aureus. Here, we describe the development of an invitro co-infection model where both viral and bacterial replication kinetics may be examined. We demonstrate CoV-2 infection does not alter bacterial interactions with host epithelial cells. In contrast, S.aureus enhances CoV-2 replication by 10- to 15-fold. We identify this pro-viral activity is due to the S.aureus iron-regulated surface determinant A (IsdA) protein and demonstrate IsdA modifies host transcription. We find that IsdA alters Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) signaling, by affecting JAK2-STAT3 levels, ultimately leading to increased viral replication. These findings provide key insight into the molecular interactions between host cells, CoV-2 and S.aureus during co-infection.

P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella.

Salmonella is an intracellular pathogen causing significant morbidity and mortality. Its ability to grow inside macrophages is important to virulence, and is dependent on the activation state of the macrophages. Classically activated M1 macrophages are non-permissive for Salmonella growth, while alternatively activated M2 macrophages are permissive for Salmonella growth. Here we showed that endotoxin-primed macrophages (MEP), such as those associated with sepsis, showed similar levels of Salmonella resistance to M1 macrophages after 2 hr of intracellular infection, but at the 4 hr and 24 hr time points were susceptible like M2 macrophages. To understand this mechanistically, transcriptomic sequencing, RNA-Seq, was performed. This showed that M1 and MEP macrophages that had not been exposed to Salmonella, demonstrated a process termed here as primed activation, in expressing relatively higher levels of particular anti-infective genes and pathways, including the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway. In contrast, in M2 macrophages these genes and pathways were largely expressed only in response to infection. Conversely, in response to infection, M1 macrophages, but not MEP macrophages, modulated additional genes known to be associated with susceptibility to Salmonella infection, possibly contributing to the differences in resistance at later time points. Application of the JAK inhibitor Ruxolitinib before infection reduced resistance in M1 macrophages, supporting the importance of early JAK-STAT signalling in M1 resistance to Salmonella.

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK–STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK–STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK–STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

TYK2 in Immune Responses and Treatment of Psoriasis.

Tyrosine kinase 2 (TYK2), a key part of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, plays an integral role in the differentiation and immune responses of intrinsic immune cells and regulates the mediation of cytokines. TYK2 leads to inflammatory cascade responses in the pathogenesis of immune-mediated inflammatory diseases (IMIDs), especially psoriasis. Small-molecule TYK2 inhibitors are considered to be an effective strategy for modulating psoriasis. Here, we attempt to review the pro-inflammatory mechanisms of the JAK-STAT signaling pathway, the regulatory roles of TYK2 in the pathogenesis of psoriasis, and provide updates on ongoing and recently completed trials of TYK2 inhibitors.

Interferon signalling contributes to therapy‐resistant prostate cancer progression

Interferon signalling contributes to therapy‐resistant prostate cancer progression

Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers.

When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.

Mechanism underlying efficacy of Shugan Sanjie decoction on plasma cell mastitis, based on network pharmacology and experimental verification.

To investigate the mechanism underpinning the effeicay of Shugan Sanjie decoction (, SGSJD) on plasma cell mastitis (PCM) based on network pharmacology, and to verify it through . Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine were used to screen effective compounds and drug targets; Online Mendelian Inheritance in Man and GeneCards were used to search for PCM targets. The potential targets of SGSJD in treating PCM were obtained after the drug targets and disease targets were crossed. Cytoscape software was used to establish and analyze the network of Chinese medicines-active compounds-targets-disease; STRING database platform was used to analyze Protein Protein Interaction network; Bioconductor software package was used to perform Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment for potential targets. Western blot analysis was used to verify the janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway . (a) 47 potential pharmacological components of SGSJD treatment of PCM were screened including quercetin, luteolin, kaempferol and others; 20 common targets were obtained, including interleukin-6 (IL-6), epidermal growth factor receptor, estrogen receptor 1, nitric oxide synthase 3 and others; a number of signal pathways were available, of which advanced glycation end product/ receptor for advanced glycation end products signaling pathway in diabetic complications, hypoxia-inducible factor 1 signaling pathway and janus tyrosine kinase-signal transducer and transcription activator (JAK-STAT) signaling pathway were the main signal pathways related to PCM. (b) Compared with the Blank group, the expressions of p-JAK2/JAK2, p-STAT3/STAT3 and IL-6 protein in the Model group were significantly increased ( < 0.01); Compared with the Model group, the expression of p-JAK2/JAK2, p-STAT3/STAT3, and IL-6 protein in the treatment group were significantly reduced in a dose-dependent manner ( < 0.05). Compared with the Model group, the dexamethasone significantly reduced the expression of p-JAK2/JAK2, p-STAT3/STAT3, and IL-6 ( < 0.01). The SGSJD may regulate the JAK-STAT signaling pathway to achieve the effect of treating PCM by reducing the expression of p-JAK2/JAK2, p-STAT3/STAT3 and IL-6 in a dose-dependent manner.

Characterization of snakehead (Channa argus) interleukin-21: Involvement in immune defense against two pathogenic bacteria, in leukocyte proliferation, and in activation of JAK–STAT signaling pathway

Interleukin-21 (IL-21), a crucial immune regulatory molecule, belongs to the common γ-chain family of type I cytokines, and exerts pleiotropic effects on multiple immune cell types in mammals. However, the characteristics and functions of fish IL-21 remain unclear. To further investigate the molecular mechanism of IL-21 in teleosts, we first cloned and identified the IL-21 gene (designated shIL-21) of the snakehead (Channa argus). The full-length open reading frame of shIL-21 is 438 bp in length, and encodes a predicted protein of 145 amino acid residues. A sequence analysis showed that shIL-21 has the typical structural characteristics of other IL-21 proteins, containing four α-helices and four conserved cysteine residues. In a phylogenetic analysis, shIL-21 clustered within a subgroup of IL-21 proteins from other teleost species and shared its closest evolutionary relationship with that of Lates calcarifer. The expression analysis showed that shIL-21 was ubiquitously expressed in all the healthy snakehead tissues tested, albeit at different levels. After infection with Nocardia seriolae or Aeromonas schubertii, the relative expression of shIL-21 was mainly upregulated in the head kidney and spleen in vivo. Similarly, after stimulation with the three pathogen analogues lipoteichoic acid, lipopolysaccharides, and polyinosinic–polycytidylic acid, the expression of shIL-21 was also induced in head kidney leukocytes in vitro. A recombinant shIL-21 protein was expressed and purified, and promoted the proliferation of head kidney leukocytes, induced the expression of genes encoding critical signaling molecules in the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway, including JAK1, JAK3, STAT1, and STAT3, and induced the expression of endogenous shIL-21 and genes encoding several key proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and IL-1β). Taken together, these preliminary findings suggest that shIL-21 is involved in the immune defense against bacterial infection, in leukocyte proliferation, and in the activation of the JAK–STAT pathway. They thus extend the functional studies of IL-21 in teleosts.

The Use of Janus Kinase Inhibitors in Axial Spondyloarthritis: Current Insights

Current pharmacological treatments of axial spondyloarthritis (axSpA) are limited to non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents, including TNFα inhibitors and IL-17 inhibitors. Despite the availability of these agents, many patients either fail to respond adequately, lose their initial therapeutic response over time, or develop undesirable side effects, thus highlighting the need for new treatment options. Janus kinase (JAK) and signal transducers and activators of transcription (STAT) are a group of intracellular kinases that play a role in the signaling pathway induced by cytokines and certain growth factors associated with the inflammatory process of axSpA. There are several lines of evidence implicating the JAK–STAT pathway in the pathophysiological process of axSpA, including genetic data, the use of certain JAK in the intracellular signal of specific cytokines involved in axSpA (IL-23, IL-22, and IL-6), and data from experimental models of SpA. This provides a rationale for the assessment of JAK inhibitors (JAKi) in clinical trials with patients with axSpA. In this review, we examine the role of JAK–STAT signaling in the pathogenesis of axSpA and summarize the results from recent clinical trials of JAKi (tofacitinib, upadacitinib, and filgotinib) in patients with axSpA.

Baricitinib treatment of severe chronic hand eczema: Two case reports

Baricitinib treatment of severe chronic hand eczema: Two case reports

The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis.

LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the amplitude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases.