STAT3 activity is necessary and sufficient for the development of immune‐mediated myocarditis in mice and promotes progression to dilated cardiomyopathy

Camporeale, Annalisa; Marino, Francesca; Papageorgiou, Anna-Pia; Carai, Paolo; Fornero, Sara; Fletcher, Steven; Page, Brent D. G.; Gunning, Patrick T.; Forni, Marco; Chiarle, Roberto; Morello, Mara; Jensen, Ole N.; Levi, Renzo; Heymans, Stéphane; Poli, Valeria

doi:10.1002/emmm.201201876

Cited by 48 publications

(42 citation statements)

References 54 publications

(101 reference statements)

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“…ALK-, C/EBPb-, and Stat3-specific shRNAs have been previously described (23,24). Retrovirus expressing NPM-ALK (25), STAT3C (26) or lentivirus expressing C/EBPb (23) have been previously described.…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

et al. 2014

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Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are defining events in several tumors, including anaplastic large-cell lymphoma (ALCL) and non-small cell lung carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared with other types of T-cell lymphoma or EGFR-and K-RAS-mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC, we found that under hypoxic conditions, ALK directly regulated the abundance of hypoxia-inducible factors (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1a and HIF2a in hypoxic conditions required ALK activity and its downstream signaling proteins STAT3 and C/EBPb. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF2a, but not HIF1a, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1a and HIF2a. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK þ tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC. Cancer Res; 74(21); 6094-106. Ó2014 AACR.

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Section: Cell Lines and Reagentsmentioning

confidence: 99%

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

et al. 2014

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“…[1][2][3] In oncology, monomeric and polymeric anti-epidermal growth factor receptor (EGFR) and anti-CD20 IgAs have demonstrated superior tumor cell killing compared to IgG, driven by FcαRI-mediated cytotoxicity or more effective receptor binding and downmodulation. [4][5][6] The cytotoxic activity of IgA could be further increased via dual engagement of both FcγR and FcαRI by IgG/A fusion or hybrid molecules. 7,8 For infectious disease, IgA multivalent target engagement enabled superior antigen binding and neutralization in influenza infection models.…”

Section: Introductionmentioning

confidence: 99%

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Lombana¹,

Rajan²,

Zorn³

et al. 2019

mAbs

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IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared to traditional IgG-based drugs. However, the transition of IgA into clinical development has been challenged by complex expression and characterization, as well as rapid serum clearance that is thought to be mediated by glycan receptor scavenging of recombinantly produced IgA monomer bearing incompletely sialylated N-linked glycans. Here, we present a comprehensive biochemical, biophysical, and structural characterization of recombinantly produced monomeric, dimeric and polymeric human IgA. We further explore two strategies to overcome the rapid serum clearance of polymeric IgA: removal of all N-linked glycosylation sites creating an aglycosylated polymeric IgA and engineering in FcRn binding with the generation of a polymeric IgG-IgA Fc fusion. While previous reports and the results presented in this study indicate that glycan-mediated clearance plays a major role for monomeric IgA, systemic clearance of polymeric IgA in mice is predominantly controlled by mechanisms other than glycan receptor clearance, such as pIgR-mediated transcytosis. The developed IgA platform now provides the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure.

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“…STAT3 in particular mediates a signal transduction that promotes cellular growth and reverses apoptosis, and thus plays a key role in neovascularization and cellular survival. Studies have shown that deletion of STAT3 in mice causes cardiomyopathy (14), and in patients with the disease, the level of STAT3 in the myocardia was significantly low (15). All these suggest that activating the JAK/STAT3 pathway may be the key to preventing the onset of heart failure.…”

Section: Discussionmentioning

confidence: 99%

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

Tamura¹,

Kohno²,

Mohri³

et al. 2018

Ann. Cardiothorac. Surg.

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Background: Previously, we have demonstrated the cardioprotective effect of interleukin (IL)-11 in animal models of acute coronary syndrome. In this study, we sought to evaluate its cardioprotective potential during prolonged hypothermic global ischemia and subsequent reperfusion using a rat heart donor model.Methods: IL-11 was administered intravenously 10 minutes before harvesting the rat heart. The hearts were preserved in cold (4 ℃) Krebs-Henseleit buffer for 6 hours, and then attached to a Langendorff perfusion apparatus and reperfused with an oxygenated Krebs-Henseleit solution containing IL-11.Normal saline was used instead of IL-11 in the control group. Functional recovery of the reperfused heart was observed by using a left ventricular balloon. Myocardial cell injury was quantified by measuring the biomarkers collected from the coronary effluent. Apoptotic cells were identified and counted using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) staining technique.Results: IL-11 administration improved myocardial function after 6 hours of cold ischemia. Although there were no significant differences in any of the baseline-measured values between the two groups, left ventricular developed pressure (LVDP) and changes in left ventricular pressures (dP/dt) were significantly higher in the IL-11 group at 120-minute reperfusion. The number of TUNEL-labeled cardiomyocytes was also significantly smaller in the IL-11 group. Conclusions:The administration of IL-11 showed a significant recovery of cardiac contractile function after 6 hours of cold ischemia. Our data suggest that it may have significant therapeutic potential for maintaining the functional viability of the heart exposed to prolonged hypothermic global ischemia.

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STAT3 activity is necessary and sufficient for the development of immune‐mediated myocarditis in mice and promotes progression to dilated cardiomyopathy

Cited by 48 publications

References 54 publications

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

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