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Investigating the role of the JAK/STAT and MAPK pathways in ischaemia/reperfusion injury and inflammation

Barry, S.P.; (2009) Investigating the role of the JAK/STAT and MAPK pathways in ischaemia/reperfusion injury and inflammation. Doctoral thesis, UCL (University College London). Green open access

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Abstract

The signal transducer and activator of transcription (STAT) proteins are a family of transcription factors which transduce extracellular signals from cytokines, growth factors and G-proteins to the nucleus. STATs become activated by phosphorylation and translocate to the the nucleus where they bind to specific target promoters. STAT1 has previously been shown to have a role in inducing apoptosis in the myocardium following ischaemia/reperfusion injury (I/R), however the role of STAT3 in myocardial apoptosis is less clear. Here it is shown that STAT3 is phosphorylated in cardiac cells both in vito and in vivo in response to I/R injury and plays a protective role by reducing the levels of apoptosis. Several modulators of STAT3 activity were found to be upregulated following I/R, including JAK2, SOCS3 and GRIM-19. STAT3 was also found to be important in regulating DNA damage and repair through altered activity of DNA damage response proteins. Administration of the antioxidant tempol in vivo, reduced infarct size in a rat model of I/R injury and this was accompanied by a reduction in STAT1 and STAT3 phosphorylation. Increasing STAT1 phosphorylation with IFN-• treatment abolished the protective effect of tempol, suggesting that inhibition of STAT1 phosphorylation may be a key protective effect of tempol infusion. Affymetrix microarray analysis of hearts from the in vivo I/R model identified several novel gene expression changes and uncovered transcriptional reduction in large numbers of genes involved in mitochondrial respiration and transport. In addition, this approach identified several possible new regulators of cardiac protection mediated by tempol and the urocortin hormones. The mitogen activated protein kinase (MAPK) family is involved in sensing cellular stress and play key roles in I/R injury and inflammation. MAPK activity is balanced by MAPK phosphatases (MKPs) such as MKP-1 and the role of MKP-1 in modulating the immune response was investigated. Mice deficient in MKP-1 were more susceptible to endotoxic shock and had elevated levels of serum cytokines. MKP-1 was found to be upregulated following toll-like recptor (TLR) stimulation and this was dependent on the signaling adaptors MyD88 and Trif. Macrophages deficient in MKP-1 had increased phosphorylation of p38 MAPK and JNK following TLR stimulation and secreted elevated amounts of the pro-inflammatory cytokines TNF-α, IL-12 and the anti-inflammatory cytokine IL-10. The temporal control and regulation of cytokine production in response to TLR stimulation was dissected using pharmacological inhibition of MAPKs. MKP-1 was not found to contribute to T cell differentiation but did have a role to play in the adaptive immune response as MKP-1- deficient mice failed to recover from an experimental model of multiple sclerosis.

Type:Thesis (Doctoral)
Title:Investigating the role of the JAK/STAT and MAPK pathways in ischaemia/reperfusion injury and inflammation
Open access status:An open access version is available from UCL Discovery
Language:English
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health

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