The Arrival of JAK Inhibitors: Advancing the Treatment of Immune and Hematologic Disorders

Furumoto, Yasuko; Gadina, Massimo

doi:10.1007/s40259-013-0040-7

Cited by 86 publications

(87 citation statements)

References 40 publications

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“…Complete blocking of IRF3 activity may conceivably prevent the stimulation of interferon and, subsequently, ISGs (Sato et al, 2000). As a comparison, we evaluated use of the JAK inhibitor tofacitinib, which is efficacious in rodent models, as well as the ER-Golgi trafficking blocker BFA (Furumotoand Gadina, 2013; Ishikawa et al, 2009). Principally, treatment of MEFs expressing STING (R284S) with tofacitinib leads to suppression of ISGs predominantly harboring STAT1 sites, such as Usp18 and Irgm2 (indicated by blue) but less suppression of genes with NF-κB and/or IRF1 transcription sites such as Cmpk2 and Rsad2, which were more evidently suppressible by GSK 690693 (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial orself-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of auto- inflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease.

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Section: Resultsmentioning

confidence: 99%

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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“…To further dissect the role of intestinal epithelial innate responses in the restriction of HuNoV infection, we investigated the effect of a specific Janus kinase 1 (JAK1)/JAK2 inhibitor on HuNoV replication in human IECs. Ruxolitinib (Rux) is a drug approved by the FDA for treatment for patients with dysregulated JAK signaling associated with myelofibrosis (36,37) and for graft-versus-host disease (GvHD) (38). Rux has also been used to enhance growth of viruses that are sensitive to IFN (39).…”

Section: Human Norovirus Replication In Intestinal Epithelial Cells Amentioning

confidence: 99%

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Hosmillo

Chaudhry

Nayak

et al. 2020

mBio

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Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system. IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.

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“…The Janus kinases (JAK) are a family of molecules consisting of a small group of receptor-associated signaling agents essential to the signal cascade originating from type I-II cytokine receptors [9]. Various studies have identified a large number of cytokines taking part in the inflammatory cascade of events taking place in psoriasis, that utilize the JAK signaling pathway [10].…”

Section: Introductionmentioning

confidence: 99%

Tofacitinib in Pediatric Psoriasis: An Open-Label Trial to Study Its Safety and Efficacy in Children

Al-Mutairi

Nour

2019

Dermatology

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Introduction: Psoriasis is a chronic, multifactorial, inflammatory disorder, with an estimated prevalence of 0.71% in children. The commonly used therapeutic agents target the underlying inflammation. Tofacitinib has demonstrated efficacy in adult psoriasis. Aim: To study the efficacy, safety, and tolerability of tofacitinib in pediatric patients with moderate to severe chronic plaque psoriasis. Methods: The study included children aged between 8 and 17 years, with moderate to severe psoriasis, given tofacitinib 5 mg orally twice daily for at least 36 weeks. The clinical response was estimated using the Psoriasis Area and Severity Index (PASI) score, Physician's Global Assessment (PGA), and the Children's Dermatology Life Quality Index (CDLQI). The incidence and severity of adverse events (AEs) were meticulously recorded in each case. Results: A total of 47 patients, with a median age of 12.3 years, completed the study. At week 12, 55.32% achieved PASI 75, and 70.21% at week 36. PGA of clear or almost clear responses at week 12 were 59.57 and 65.96%, respectfully, at week 36. Relatively few and mostly minor adverse effects were noted. No severe AEs were reported. Conclusion: The treatment with tofacitinib was safe and well tolerated, and led to significant improvement of their disease and quality of life as reflected in CDLQI scores. However, the results need to be validated in larger multicenter trials.

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The Arrival of JAK Inhibitors: Advancing the Treatment of Immune and Hematologic Disorders

Cited by 86 publications

References 40 publications

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Tofacitinib in Pediatric Psoriasis: An Open-Label Trial to Study Its Safety and Efficacy in Children

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