Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Gómez-Valadés, Alícia G.; Llamas, María A.; Blanch, Sílvia; Perales, José C.; Román, Juan José Mora; Gómez-Casajús, Lluís; Mascaró, Cristina

doi:10.1038/mtna.2012.37

Cited by 13 publications

(6 citation statements)

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“…plasmids and siRnAs. The sequences for siJAK3 were 5′-GGGUCCUUCACCAAGAUUU-3′ and 5′-CCAUGGUGCAGGAAUUUGU-3′ (Dharmacon Inc) 41 , and RNAiMAX (Invitrogen) was employed as the transfection reagent following the supplier's recommended protocol, where non-targeting siRNA (Dharmacon, D-001210-02-20) was the control. The MIG and the MIG-JAK3 (wild-type) plasmids were kindly provided by Dr. Kara Johnson at Oregon Health and Science University.…”

Section: Discussionmentioning

confidence: 99%

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

Miao

Liu

et al. 2020

Sci Rep

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Kinases are involved in numerous critical cell signaling processes, and dysregulation in kinase signaling is implicated in many types of human cancers. in this study, we applied a parallel-reaction monitoring (pRM)-based targeted proteomic method to assess kinome reprogramming during melanoma metastasis in three pairs of matched primary/metastatic human melanoma cell lines. Around 300 kinases were detected in each pair of cell lines, and the results showed that Janus kinase 3 (JAK3) was with reduced expression in the metastatic lines of all three pairs of melanoma cells. interrogation of The Cancer Genome Atlas (TCGA) data showed that reduced expression of JAK3 is correlated with poorer prognosis in melanoma patients. Additionally, metastatic human melanoma cells/tissues exhibited diminished levels of JAK3 mRNA relative to primary melanoma cells/tissues. Moreover, JAK3 suppresses the migration and invasion of cultured melanoma cells by modulating the activities of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). In summary, our targeted kinome profiling method provided by far the most comprehensive dataset for kinome reprogramming associated with melanoma progression, which builds a solid foundation for examining the functions of other kinases in melanoma metastasis. Moreover, our results reveal a role of JAK3 as a potential suppressor for melanoma metastasis.

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Section: Discussionmentioning

confidence: 99%

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

Miao

Liu

et al. 2020

Sci Rep

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“…In previous studies, a critical role for JAK1 was identified as STAT6 was activated by IL-4 or IL-13 through JAK1 in rat alveolar type II cells and airway epithelial cells were shown to require IL-4 signaling after allergen exposure (44, 45). Although a predominant role for JAK3 over JAK1 was suggested from siRNA knockdown experiments (46), intracellular enzymatic levels of JAK1 were shown to be higher than levels of JAK3 (47). This dissociation might reflect differences in individual JAK kinase binding capabilities to substrates or ligands versus enzymatic activities.…”

Section: Discussionmentioning

confidence: 99%

Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses

Ashino

Takeda

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Janus kinases (JAK) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on Th2 differentiation and development of lung allergic responses has not been investigated. Objective To examine a selective JAK1/3 inhibitor (R256) on differentiation of Th subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma. Methods A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of Th1, Th2, and Th17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or during allergen challenge phases in the primary challenge model or just prior to provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge. Results In vitro, R256 inhibited differentiation of Th2 but not Th1 or Th17 cells, associated with downregulation of STAT6 and STAT5 phosphorylation. However, once polarized, Th2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented development of AHR, airway eosinophilia, mucus hypersecretion, and Th2 cytokine production without changes in Th1 and Th17 cytokine levels, indicating that selective blockade of Th2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in Th2 cytokine production, suggesting the inhibitory effects were downstream of Th2 cytokine receptor signaling pathways. Conclusions Targeting the Th2-dependent JAK-STAT activation pathway represents a novel therapeutic approach for the treatment of asthma. Clinical Implications Targeting JAK1/3 signaling pathways provides a novel intervention for preventing allergen-induced alterations in lung function. Capsule Summary JAK1/3 signaling pathways are essential for initiation of Th2 differentiation and the development of lung allergic responses.

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“…For instance, electroporation and nucleofection cause excessive cell death and may require preactivation of T cells and electrical apparatus [ 108 , 109 ]. Chemically modified synthetic siRNA with Acell agents can be transfected into primary T cells; however, they are needed to incubate with T cells for longer time and only a small portion of T cells are transfected [ 110 ]. The most disappointing defect of these methods is that it is difficult for them to be used in vivo .…”

Section: Targeting Th17 Cells By Cd4 Aptamer-ror γ mentioning

confidence: 99%

Targeting Th17 Cells with Small Molecules and Small Interference RNA

Lin

Song

Zhao

et al. 2015

Mediators of Inflammation

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T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX) technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4+ T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

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Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Cited by 13 publications

References 50 publications

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses

Targeting Th17 Cells with Small Molecules and Small Interference RNA

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