Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice

Durán, José Gabriel Barcia; Lu, Tyler M.; Houghton, Sean; Geng, Fuqiang; Schreiner, Ryan; Xiang, Jenny; Rafii, Shahin; Redmond, David; Lis, Raphaël

doi:10.1038/s42003-021-01846-3

Cited by 13 publications

(2 citation statements)

References 102 publications

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“…Although trials were withdrawn due to higher rates of viral infection and malignancy 26,27 , there is continued interest in the potential application of other JAK inhibitors with improved safety profiles for transplant immunosuppression 28,29 . JAK3 is preferentially expressed in T and NK cells, but not widely in the endothelium 30 . New studies are evaluating JAK1/2 inhibitors in select SOTx recipient populations, such as those with carcinoma [NCT04807777] or with chronic bronchiolitis obliterans syndrome post-lung transplant [NCT03978637].…”

Section: Discussionmentioning

confidence: 99%

Endothelial Resolution of Inflammation is Delayed Following JAK-driven but not NFκB-dependent Activation

Valenzuela

2021

Preprint

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Blood endothelial cells actively regulate egress of leukocytes into peripheral tissues in response to inflammatory insult. The resolution of inflammation is critical for healing and return to homeostasis, but the timing and mechanisms involved in return to a non-inflamed state are not well-understood. We examined vascular endothelial activation comparing NFκB-driven TNFα and JAK/STAT-mediated IFNγ. Pro-adhesive gene expression, phenotype and secretome of human endothelial cells from 6 vascular beds were measured under chronic cytokine stimulation, and after short-term cytokine priming followed by withdrawal. The majority of inducible TNFα effectors require continuous exposure for reinforcement of the altered phenotype. NFκB and target genes are quickly down-regulated in the absence of cytokine. In contrast, the consequences of even short exposure to IFNγ are long-lasting and broad, with sustained elevation of adhesion molecules and chemokines up to 48hr later. JAK/STAT and interferon response factor expression are likewise durable, dependent on new transcription and autonomous of continuous IFNγ. Finally, intact persistent STAT expression and JAK signaling in the endothelium is required to maintain a pro-adhesive phenotype after IFNγ withdrawal, which could be prevented by the JAK1/2 inhibitor ruxolitinib. Our results reveal a sustained JAK-dependent perturbation of endothelial function after exposure to IFNγ, but not after NFκB-driven inflammation.

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Section: Discussionmentioning

confidence: 99%

Endothelial Resolution of Inflammation is Delayed Following JAK-driven but not NFκB-dependent Activation

Valenzuela

2021

Preprint

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“…[48][49][50][51][52][53] JAK3 is expressed at high levels predominantly in hematopoietic cells, whereas the other members are widely expressed in many tissues. 54,55 The JAK proteins are composed of the FERM (the complex of four point one, ezrin, radixin, and moesin), Src homology domain (SH2), pseudokinase, and kinase domains. [56][57][58] The FERM domain has a clover structure composed of F1, F2, and F3 substructures.…”

Section: Jak Stat and The Jak-stat Pathwaymentioning

confidence: 99%

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Xue

Yao

et al. 2023

Sig Transduct Target Ther

138

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The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

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Exploring characteristics of placental transcriptome and cord serum metabolome associated with low birth weight in Kele pigs

Zhang,

Wu,

et al. 2023

Trop Anim Health Prod

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Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice

Cited by 13 publications

References 102 publications

Endothelial Resolution of Inflammation is Delayed Following JAK-driven but not NFκB-dependent Activation

Endothelial Resolution of Inflammation is Delayed Following JAK-driven but not NFκB-dependent Activation

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Exploring characteristics of placental transcriptome and cord serum metabolome associated with low birth weight in Kele pigs

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