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Title: Interleukin-37 isoform A (IL-37a) is a novel regulator of immune cell function
Author: Hameed, Najwa Jameel
ISNI:       0000 0004 7963 147X
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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Background: Interleukin (IL)-37 is a newly identified member of IL-1 cytokine family, and has five isoforms (IL-37a-e). While the function of IL-37b has been well studied as an important immunosuppressive cytokine that plays an antiinflammatory role in several diseases, the functions of other IL-37 isoforms are largely unknown. The five IL-37 isoforms are varying in protein sequences, induction and tissue distribution, suggesting that the isoforms may differ in function. This study was focusedon the IL-37a isoform, with IL-37b as a control. This was because our preliminary results showed that IL-37a expression is highly inducible in human macrophages by inflammatory stimuli compared to other IL37 isoforms, suggesting that IL-37a may play an important role in inflammatory response. Furthermore, IL-37a protein is different from other IL-37 isoforms, in particular the N- terminal which contains a nuclear localisation sequence (NLS) and an elastase cleave site, suggesting that IL-37a may have unique biochemical features and functions. Hypothesis: Based on the differences at the N-terminal, IL-37a and IL-37b isoforms may differ in cellular location and function. Based on protein sequence similarities with IL-37b at the C-terminal, which contains the IL-1 domain for receptor binding and signalling. IL-37a may be also bioactive by signalling via the same receptor as IL-37b. Aim: To address the hypothesis, I set out the following aims: 1) to produce recombinant IL-37a and IL-37b proteins and compare their differences in protein levels (Chapter 3). 2) To investigate whether IL-37a is bioactive and what is the difference between IL-37a and b in the regulation of Toll-like receptor (TLR)- induced inflammatory response in immune cells (Chapter 4). 3) To explore the molecular mechanism by which IL-37a and b differently regulate inflammatory gene profiles and signalling pathways by transcriptomics. Methods: To investigate their effect and difference in bioactivity, I produced recombinant IL-37a and b in Escherichia coli (E.coli) system and purified by affinity chromatography and gel filtration (Chapter 3). The effect of IL-37a and IL-37b on the regulation of TLR-induced inf ii compared in macrophages and in B cells in vitro (Chapter 4). The B cells from IL37a transgenic (IL-37a-tg) mice and wild type (wt) control mice were used for studying the effect of IL-37a on B cell functions (Chapter 4). The microarray and bioinformatics analysis was used to unravel the differences between IL-37a and b in term of genes regulation and signalling pathways in lipopolysaccharide (LPS)- stimulated spleenocytes from IL37a and b transgenic and wt control mice (Chapter 5).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH345 Biochemistry