JAK/STAT Signaling: From Mechanisms to Emerging Therapeutics

Recent progress has been made on the role of oncoproteins c-Ski and related SnoN in the control of cellular transformation. c-Ski/SnoN potently repress transforming growth factor-beta (TGF-beta) antiproliferative signaling through physical interaction with signal transducers called Smads. Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown. During our investigation on the role of sumoylation in TGF-beta signaling, we inadvertently found that SnoN is modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-beta signaling. Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.

An important component of the innate immune response of the host in viral infection is the production of type I interferons. Efforts to understand the molecular mechanisms by which animal viruses and also double-stranded RNA trigger the induction of interferon (IFN) 2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon.2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon. have led to the identification of cellular sensors of viral infection. The first two minireviews in this issue provide updates on two kinds of nucleic acid sensors and the biochemical pathways by which they signal the production of interferon. One type of sensor is the family of cytosolic receptor proteins (RIG-I, MDA5, LGP2) known as the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR). The other type of sensor includes members of the Toll-like receptor (TLR) family of cell surface and endosomal membrane protein receptors (TLR3, -7, -8, and -9). These minireviews focus on the biochemical and cellular aspects of the signaling pathways activated by RNA, both single-stranded (ss) RNA and double-stranded (ds) RNA, including the nature of the RLR and TLR sensor proteins and the adaptors through which they signal the production of IFN in virus-infected cells. The third minireview focuses on the structure and function of interferon regulatory factor (IRF) 3 and, to an extent, IRF-7, which are activated by the RLR and TLR signaling pathways. These IRFs, together with the nuclear factor-κB (NF-κB) and activator protein 1 factors lead to the transcriptional activation of the type I interferon β (IFN-β) gene.Interferon was discovered as an antiviral cytokine 50 years ago during seminal studies on virus interference (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar). We now have considerable knowledge about the biology and biochemistry of the IFN system and the critically important role that IFN plays in the innate immune response (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2115) Google Scholar). Most recently, exciting progress has been made toward elucidating the biochemical pathways by which the host recognizes invading viral pathogens and triggers the production of the type I IFNs, principally IFN-β. Aspects of the RLR and TLR signaling pathways leading to the induction of type I IFN expression in response to viral nucleic acids are summarized in Fig. 1. The RIG-I-like receptors signal via the mitochondrial membrane-associated interferon promoter stimulator 1 (IPS-1) adaptor protein. The Toll-like receptors signal via either the TRIF (Toll/interleukin 1 receptor domain-containing adaptor protein inducing IFN-β) adaptor protein in the case of TLR3 or the MyD88 (myeloid differentiation primary response protein 88) adaptor protein in the case of TLR7, -8, and -9. These signaling pathways lead to the activation of IRF and NF-κB factors that play a key role in the induction of type I IFN expression.In the first minireview, Mitsutoshi Yoneyama and Takashi Fujita at Kyoto University in their article entitled "Function of RIG-I-like Receptors in Antiviral Innate Immunity" consider new developments in both the biochemistry and biology of the cellular RIG-I helicase family of RNA sensors (3Yoneyama M. Fujita T. J. Biol. Chem. 2007; 282: 15315-15318Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The functional domains and activities of the RLRs, the nature of the viral RNAs that trigger IFN production in an RLR-dependent manner, the proteins that constitute the RLR signaling pathway, and the antagonism of RLR signaling by viral gene products are discussed.The second minireview of the series by Satoshi Uematsu and Shizuo Akira at Osaka University entitled "Toll-like Receptor and Type I Interferons" focuses on recent developments in understanding the TLR receptors that recognize viral nucleic acids including TLR3, which recognizes dsRNA; TLR7 and TLR8, which recognize G- and U-rich ssRNAs; and TLR9, which recognizes CpG-containing DNA (4Uematsu S. Akira S. J. Biol. Chem. 2007; 282: 15319-15324Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). In addition, progress in understanding the cell surface recognition of viral envelope components by TLR4 leading to IFN induction is discussed. The roles of the RLRs and individual TLRs are considered in the production of IFN-β and IFN-α in different types of cells, including fibroblasts, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs).The final minireview of this thematic series on triggers of antiviral innate immunity focuses on the centrally important IRFs involved in transcriptional activation of the type I interferon gene promoters. John Hiscott at McGill University in his minireview entitled "Triggering the Innate Antiviral Response through IRF-3 Activation" describes the role that the transcription factor IRF-3, as well as the closely related factor IRF-7, play in the RLR-dependent and TLR-dependent signaling pathways (5Hiscott J. J. Biol. Chem. 2007; 282: 15325-15329Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar).Much progress has been made in elucidating the biochemical mechanisms by which viral infection causes the transcriptional activation of type I interferon production through the RIG-I-like receptor and Toll-like receptor signaling pathways. The authors and editors hope that this minireview series on antiviral innate immunity will enable researchers in the basic and clinical sciences to better appreciate the signaling pathways and the mechanistic insights gained in the area of viral recognition by RLRs and TLRs leading to the expression of type I interferon genes. An important component of the innate immune response of the host in viral infection is the production of type I interferons. Efforts to understand the molecular mechanisms by which animal viruses and also double-stranded RNA trigger the induction of interferon (IFN) 2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon.2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon. have led to the identification of cellular sensors of viral infection. The first two minireviews in this issue provide updates on two kinds of nucleic acid sensors and the biochemical pathways by which they signal the production of interferon. One type of sensor is the family of cytosolic receptor proteins (RIG-I, MDA5, LGP2) known as the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR). The other type of sensor includes members of the Toll-like receptor (TLR) family of cell surface and endosomal membrane protein receptors (TLR3, -7, -8, and -9). These minireviews focus on the biochemical and cellular aspects of the signaling pathways activated by RNA, both single-stranded (ss) RNA and double-stranded (ds) RNA, including the nature of the RLR and TLR sensor proteins and the adaptors through which they signal the production of IFN in virus-infected cells. The third minireview focuses on the structure and function of interferon regulatory factor (IRF) 3 and, to an extent, IRF-7, which are activated by the RLR and TLR signaling pathways. These IRFs, together with the nuclear factor-κB (NF-κB) and activator protein 1 factors lead to the transcriptional activation of the type I interferon β (IFN-β) gene. Interferon was discovered as an antiviral cytokine 50 years ago during seminal studies on virus interference (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar). We now have considerable knowledge about the biology and biochemistry of the IFN system and the critically important role that IFN plays in the innate immune response (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2115) Google Scholar). Most recently, exciting progress has been made toward elucidating the biochemical pathways by which the host recognizes invading viral pathogens and triggers the production of the type I IFNs, principally IFN-β. Aspects of the RLR and TLR signaling pathways leading to the induction of type I IFN expression in response to viral nucleic acids are summarized in Fig. 1. The RIG-I-like receptors signal via the mitochondrial membrane-associated interferon promoter stimulator 1 (IPS-1) adaptor protein. The Toll-like receptors signal via either the TRIF (Toll/interleukin 1 receptor domain-containing adaptor protein inducing IFN-β) adaptor protein in the case of TLR3 or the MyD88 (myeloid differentiation primary response protein 88) adaptor protein in the case of TLR7, -8, and -9. These signaling pathways lead to the activation of IRF and NF-κB factors that play a key role in the induction of type I IFN expression. In the first minireview, Mitsutoshi Yoneyama and Takashi Fujita at Kyoto University in their article entitled "Function of RIG-I-like Receptors in Antiviral Innate Immunity" consider new developments in both the biochemistry and biology of the cellular RIG-I helicase family of RNA sensors (3Yoneyama M. Fujita T. J. Biol. Chem. 2007; 282: 15315-15318Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The functional domains and activities of the RLRs, the nature of the viral RNAs that trigger IFN production in an RLR-dependent manner, the proteins that constitute the RLR signaling pathway, and the antagonism of RLR signaling by viral gene products are discussed. The second minireview of the series by Satoshi Uematsu and Shizuo Akira at Osaka University entitled "Toll-like Receptor and Type I Interferons" focuses on recent developments in understanding the TLR receptors that recognize viral nucleic acids including TLR3, which recognizes dsRNA; TLR7 and TLR8, which recognize G- and U-rich ssRNAs; and TLR9, which recognizes CpG-containing DNA (4Uematsu S. Akira S. J. Biol. Chem. 2007; 282: 15319-15324Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). In addition, progress in understanding the cell surface recognition of viral envelope components by TLR4 leading to IFN induction is discussed. The roles of the RLRs and individual TLRs are considered in the production of IFN-β and IFN-α in different types of cells, including fibroblasts, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs). The final minireview of this thematic series on triggers of antiviral innate immunity focuses on the centrally important IRFs involved in transcriptional activation of the type I interferon gene promoters. John Hiscott at McGill University in his minireview entitled "Triggering the Innate Antiviral Response through IRF-3 Activation" describes the role that the transcription factor IRF-3, as well as the closely related factor IRF-7, play in the RLR-dependent and TLR-dependent signaling pathways (5Hiscott J. J. Biol. Chem. 2007; 282: 15325-15329Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar). Much progress has been made in elucidating the biochemical mechanisms by which viral infection causes the transcriptional activation of type I interferon production through the RIG-I-like receptor and Toll-like receptor signaling pathways. The authors and editors hope that this minireview series on antiviral innate immunity will enable researchers in the basic and clinical sciences to better appreciate the signaling pathways and the mechanistic insights gained in the area of viral recognition by RLRs and TLRs leading to the expression of type I interferon genes.

From the earliest phases of life, such as embryonic development, to serious illnesses including cancer, heart attacks, strokes, and wound healing, angiogenesis plays a crucial function in the human body. Numerous pharmaceutical companies have made significant investments in both the activation and inhibition of angiogenesis. The nanotechnology revolution has had a significant impact on medicine over the past ten years, and nanomedicines are beginning to receive regulatory authorization to treat a variety of ailments. In oncology and ophthalmology, angiogenesis is inhibited, while in tissue engineering and wound healing, angiogenesis is stimulated. This review tries to summarize the various angiogenesis-related nanotechnology-based approaches that have been studied. A variety of inorganic and metallic nanoparticles, including lipid-, carbon-, and polymeric[1]. Angiogenesis: Mechanisms, Regulation, and Therapeutic Perspectives. Angiogenesis, the process of new blood vessel formation, plays a crucial role in various physiological and pathological conditions. This complex phenomenon is tightly regulated by an interplay of pro- and anti-angiogenic factors, orchestrating the growth and remodeling of vascular networks. In normal physiological processes such as embryonic development, wound healing, and tissue repair, angiogenesis is a vital mechanism to ensure tissue perfusion and oxygenation. However, dysregulated angiogenesis is implicated in numerous diseases, including cancer, cardiovascular disorders, and chronic inflammatory conditions. In cancer, the formation of new blood vessels sustains tumor growth and metastasis, making angiogenesis an attractive target for therapeutic interventions. Understanding the underlying molecular mechanisms and signaling pathways that drive angiogenesis has been instrumental in developing targeted therapies aimed at inhibiting or promoting angiogenesis, depending on the clinical context. We summarize the current knowledge surrounding angiogenesis, focusing on its regulatory factors and signaling pathways. We delve into the critical roles of vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), angiopoietins, and other key players in modulating angiogenic processes. Additionally, we explore the role of endothelial cells and pericytes in vascular stabilization and vessel maturation.

Glial cell missing Drosophila homolog a (GCMa) is an essential transcription factor for placental development, which controls the differentiation of the syncytiotrophoblast layer. Although the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery, specifically interacts with the N-terminal domain of GCMa and promotes GCMa sumoylation on lysine 156. Moreover, GCMa-mediated transcriptional activation was repressed by sumoylation but was enhanced in the presence of the SUMO-specific protease, SENP1. The repressive effect of sumoylation on GCMa transcriptional activity was attributed to decreased DNA binding activity of GCMa. Furthermore, structural analysis revealed a steric clash between the SUMO1 moiety of sumoylated GCMa and the DNA-binding surfaces of GCMa, which may destabilize the interaction between GCMa and its cognate DNA sequence. Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation.

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a pivotal role in B cell biology and function. As an essential component of the B cell receptor (BCR) signaling pathway, BTK is expressed not only in B cells but also in myeloid cells, including monocytes/macrophages, dendritic cells, neutrophils, and mast cells. BTK inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. Besides their well-characterized role in inhibiting BCR signaling, BTKis also exert significant immunological influences outside the tumor cell that extend their therapeutic potential and impact on the immune system in different ways. This work elucidates the immunomodulatory mechanisms associated with BTK inhibition, focusing on CLL and other clinical contexts. We discuss how BTK inhibition affects various immune cells, including B cells, T cells, and macrophages. The effects of BTKis on the profiles of cytokines, also fundamental parts of the tumor microenvironment (TME), are summarized here as well. This review also appraises the implications of these immunomodulatory actions in the management of autoimmune diseases and infections. Summarizing the dual role of BTK inhibition in modulating malignant lymphocyte and immune cell functions, this paper highlights the broader potential clinical use of compounds targeting BTK.

Nrf2 is the main transcriptional controller of cellular oxidative stress responses. This is achieved by driving the transcription of a battery of cytoprotective genes that possess a characteristic Antioxidant Response Element (ARE) sequence in their upstream promoter regions. As such, the Nrf2 signalling pathway plays a vital role in health, aging and disease. Defects in Nrf2 activity can lead to impaired mitochondrial function and reduced protection against free radical damage. Over time these effects contribute to common age-related conditions including cardiovascular disease, neurodegeneration and chronic inflammatory conditions. Despite the well-characterised cytoprotective role of Nrf2, inappropriate over or under activation of Nrf2 signalling can also be detrimental. It is therefore important to develop a better understanding of how Nrf2 signalling networks may be regulated. For that reason, the primary aim of this project was to provide a better systems level contextual understanding of Nrf2 signalling in human cells, by generating an improved high-density experimentally defined human Nrf2-centric protein-protein interaction network. Under normal basal conditions Nrf2 binds to Keap1, a component of the Cul3/Rbx1 ubiquitin ligase complex, resulting in a constant process of Nrf2 ubiquitination and proteasomal degradation. However, under conditions of oxidative stress or pharmacological intervention, Keap1 becomes modified, thus altering the interaction with Nrf2 and allowing newly synthesised Nrf2 to be transported into the nucleus, resulting in the transcription of a diverse range of ARE-driven cytoprotective genes. While this simple process appears to operate in most cells, Nrf2 and Keap1 both have many more known and predicted interaction partners. Additionally, other components of the Nrf2 cascade are known to interact with components of other pathways and signalling networks such as the NF-ĸB complex. Currently it is not clear which of these interactions are competitive, sequential or conditional; or how these proteins may work together in multi-protein complexes. By addressing these questions we will be able to provide better insight into the detailed molecular mechanism of Nrf2 signalling and the potential effects of crosstalk between different signalling cascades in human cells. Protein-protein interaction (PPI) networks can also provide insight into the function of uncharacterised proteins and can guide future hypothesis driven research into protein function and the regulation of complex biological processes. PPI data for Nrf2 remains unclear and incomplete, therefore a predicted Nrf2 PPI network was initially generated from publically available datasets, an ‘in-house’ interactome and from literature. The yeast two-hybrid system was then initially employed to test 135 predicted binary interactions and identify novel Nrf2 interaction partners. A combination of secondary interaction methods and transcriptional activity assays were then used to assess confidence limits for Nrf2 partner interaction profiles. Finally, conditional changes in Nrf2 protein complex profiles were investigated in a series of Affinity Purification coupled with Mass Spectrometry assays. This study identified 98 novel experimentally defined binary Nrf2 interaction partners using the yeast two-hybrid assays, together with 96 novel interactions from the Mass Spectrometry studies. This increased the complexity of the binary Nrf2 PPI network by almost 4-fold, and the total Nrf2 interactome by 3.7- fold. This Nrf2-centric network can be used to guide future hypothesis driven research into the physiological mechanisms and functional relevance of these interactions, providing a more in-depth understanding of the molecular mechanisms of Nrf2 regulation and pathway crosstalk in human cells.

SUMO conjugation of cellular proteins is essential for proper progression of mitosis. PIASy, a SUMO E3 ligase, is required for mitotic SUMOylation of chromosomal proteins, yet the regulatory mechanism behind the PIASy-dependent SUMOylation during mitosis has not been determined. Using a series of truncated PIASy proteins, we have found that the N terminus of PIASy is not required for SUMO modification in vitro but is essential for mitotic SUMOylation in Xenopus egg extracts. We demonstrate that swapping the N terminus of PIASy protein with the corresponding region of other PIAS family members abolishes chromosomal binding and mitotic SUMOylation. We further show that the N-terminal domain of PIASy is sufficient for centromeric localization. We identified that the N-terminal domain of PIASy interacts with the Rod/Zw10 complex, and immunofluorescence further reveals that PIASy colocalizes with Rod/Zw10 in the centromeric region. We show that the Rod/Zw10 complex interacts with the first 47 residues of PIASy which were particularly important for mitotic SUMOylation. Finally, we show that depletion of Rod compromises the centromeric localization of PIASy and SUMO2/3 in mitosis. Together, we demonstrate a fundamental mechanism of PIASy to localize in the centromeric region of chromosome to execute centromeric SUMOylation during mitosis.

Obstructive Sleep Apnea (OSA) is a disorder characterized by repeated upper airway collapse during sleep, leading to apneas and/or hypopneas, with associated symptoms like intermittent hypoxia and sleep fragmentation. One of the agents contributing to OSA occurrence and development seems to be serotonin (5-HT). Currently, the research focuses on establishing and interlinking OSA pathogenesis and the severity of the disease on the molecular neurotransmitter omnipresent in the human body-serotonin, its pathway, products, receptors, drugs affecting the levels of serotonin, or genetic predisposition. The 5-HT system is associated with numerous physiological processes such as digestion, circulation, sleep, respiration, and muscle tone-all of which are considered factors promoting and influencing the course of OSA because of correlations with comorbid conditions. Comorbidities include obesity, physiological and behavioral disorders as well as cardiovascular diseases. Additionally, both serotonin imbalance and OSA are connected with psychiatric comorbidities, such as depression, anxiety, or cognitive dysfunction. Pharmacological agents that target 5-HT receptors have shown varying degrees of efficacy in reducing the Apnea-Hypopnea Index and improving OSA symptoms. The potential role of the 5-HT signaling pathway in modulating OSA provides a promising avenue for new therapeutic interventions that could accompany the primary treatment of OSA-continuous positive airway pressure. Thus, this review aims to elucidate the complex role of 5-HT and its regulatory mechanisms in OSA pathophysiology, evaluating its potential as a therapeutic target. We also summarize the relationship between 5-HT signaling and various physiological functions, as well as its correlations with comorbid conditions.

Autism spectrum disorder (ASD1) is a behaviorally defined syndrome encompassing a markedly heterogeneous patient population. Many ASD subjects fail to respond to the 1st line behavioral and pharmacological interventions, leaving parents to seek out other treatment options. Evidence supports that neuroinflammation plays a role in ASD pathogenesis. However, the underlying mechanisms likely vary for each ASD patient, influenced by genetic, epigenetic, and environmental factors. Although anti-inflammatory treatment measures, mainly based on metabolic changes and oxidative stress, have provided promising results in some ASD subjects, the use of such measures requires the careful selection of ASD subjects based on clinical and laboratory findings. Recent progress in neuroscience and molecular immunology has made it possible to allow re-purposing of currently available anti-inflammatory medications, used for autoimmune and other chronic inflammatory conditions, as treatment options for ASD subjects. On the other hand, emerging anti-inflammatory medications, including biologic and gate-keeper blockers, exert powerful anti-inflammatory effects on specific mediators or signaling pathways. It will require both a keen understanding of the mechanisms of action of such agents and the careful selection of ASD patients suitable for each treatment. This review will attempt to summarize the use of anti-inflammatory agents already used in targeting ASD patients, and then emerging anti-inflammatory measures applicable for ASD subjects based on scientific rationale and clinical trial data, if available. In our experience, some ASD patients were treated under diagnoses of autoimmune/autoinflammatory conditions and/or post-infectious neuroinflammation. However, there are little clinical trial data specifically for ASD subjects. Therefore, these emerging immunomodulating agents for potential use for ASD subjects will be discussed based on preclinical data, case reports, or data generated in patients with other medical conditions. This review will hopefully highlight the expanding scope of immunomodulating agents for treating neuroinflammation in ASD subjects.

Chapter 10 - Targeting Th17 and Treg Signaling Pathways in Autoimmunity

The tumor suppressor, p53, plays critical roles in the cell cycle progression, DNA repair and apoptosis. The PIAS proteins (protein inhibitor of activated STAT) were originally identified as inhibitors of the JAK-STAT pathway. Subsequently, crosstalk between the PIAS proteins and other signaling pathways has been shown to be involved in various cellular processes. Particularly, previous studies have demonstrated that PIAS proteins regulate p53-mediated transcription through sumoylation. hZimp10, also named zmiz1, is a novel PIAS-like protein and functions as a transcriptional co-activator. We recently identified p53 to be an hZimp10 interacting protein in the yeast two-hybrid screen. The interaction between p53 and hZimp10 was confirmed by GST pull-down and co-immunoprecipitation assays. Co-localization of p53 and hZimp10 proteins was also observed within cell nuclei by immunostaining. Moreover, we show that expression of exogenous hZimp10 enhances the transcriptional activity of p53 and knockdown of endogenous hZimp10 reduces the transcriptional activity of p53. Furthermore, using chromatin immunoprecipitation assays, we demonstrate that hZimp10 binds to p53 on the p21 promoter. Finally, p53-mediated transcription is significantly impaired in Zimp10 null embryonic fibroblasts. Taken together, these results provide the first line of evidence to demonstrate a role for Zimp10 in regulating p53 function.

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.

Cepharanthine, a biscolaurine alkaloid isolated from the plant Stephania cephalantha Hayata, has been reported to have potent anti-inflammatory properties. Here, we investigated the effects of cepharanthine on the expression of CXCL10 (a CXC chemokine induced by interferon-gamma [IFN-γ] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN-γ-treated human salivary gland cell lines. We observed that IFN-γ-induced CXCL10 production in NS-SV-DC cells (a human salivary gland ductal cell line), but not in NS-SV-AC cells (a human salivary gland acinar cell line). Cepharanthine inhibited the IFN-γ-induced CXCL10 production in NS-SV-DC cells. A Western blot analysis showed that cepharanthine prevented the phosphorylation of JAK2 and STAT1, but did not interfere with the NF-κB pathway. Moreover, cepharanthine inhibited the IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN-γ-induced CXCL10 production via the inhibition of the JAK2/STAT1 signaling pathway in human salivary gland ductal cells. Our findings also indicate that cepharanthine could inhibit the chemotaxis of Jurkat T cells by reducing CXCL10 production.

The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is essential for controlling immune function, blood cell formation, and cell growth. Dysregulation of this pathway is implicated in various diseases, including hematologic malignancies, autoimmune disorders, and chronic inflammatory conditions. This review provides a comprehensive overview of the structural and functional aspects of JAK/STAT signaling, with a particular focus on the role of JAK2. This manuscript explores the primary regulators of the JAK/STAT pathway, such as Suppressors Of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS), and Protein Tyrosine Phosphatases (PTPs), which play a crucial role in maintaining cellular balance and stability. Additionally, the therapeutic landscape of JAK2 inhibitors is explored, covering both approved and investigational drugs, including their mechanisms of action, efficacy, and safety profiles. Emerging strategies such as drug repositioning using computational approaches and experimental validation are also highlighted. By integrating insights from molecular docking studies, machine learning models, and kinase assays, this review emphasizes the potential of JAK2 inhibitors in disease management.

Phosphodiesterases (PDEs) and their substrates, cAMP and cGMP, are ubiquitously expressed in the immune system. Inhibiting PDEs may represent a novel approach for regulating immune functions and have a therapeutic potential in the management of autoimmune diseases. Phosphodiesterase inhibitors (PDEi) have proved effective in clinical trials in the management of pulmonary artery hypertension and Raynaud's phenomenon. Data from animal models suggest that the immunomodulatory effect of PDEi may have a therapeutic potential in the management of diseases such as multiple sclerosis and rheumatoid arthritis. The antifibrotic potential of PDEi, as suggested by animal experiments, if proven in further studies will be a major step in the treatment of fibrosing diseases such as scleroderma and idiopathic pulmonary fibrosis. Drug Dev Res 72:772–778, 2011. © 2011 Wiley Periodicals, Inc.