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Mechanisms by which interleukin-4 suppresses inflammatory cytokine production by activated human monocytes

Woodward, Eleanor (2011) Mechanisms by which interleukin-4 suppresses inflammatory cytokine production by activated human monocytes. PhD thesis, Murdoch University.

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Abstract

Improving understanding of how inflammatory responses by monocytes and macrophages are regulated may aid in the development of more targeted therapies for chronic inflammatory disease. In this thesis the mechanisms by which the cytokine, IL-4, can suppress inflammatory cytokine production by LPS-stimulated human monocytes have been examined.

IL-4 suppressed LPS-induced TNFα transcription, without inhibiting LPS signalling through IκB, the mitogen-activated protein kinase (MAPK) pathways, or LPS-mediated activation of the transcription factor NF-κB. Histone acetylation regulated LPS-induced cytokine production but not the suppression of these cytokines by IL-4. IL-4 induced three molecules with potential anti-inflammatory properties, suppressor of cytokine signalling-1 (SOCS1), peroxisome proliferator-activated receptor gamma (PPARγ) and triggering receptors expressed on myeloid cells-2 (TREM-2), but suppressed LPS-induced TNFα production independently of these molecules.

Targeted gene arrays for Toll-like receptor (TLR) signalling pathways revealed that IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering other NF-κB-dependent genes or mRNA levels of TLR-related signalling molecules. Instead, the anti-inflammatory actions of IL-4 may be mediated by up-regulation of an unknown signalling molecule or transcriptional regulator. In LPS-treated monocytes, IL-4 up-regulated mRNA levels for IL-10, receptor-interacting serine-threonine kinase 2 (RIPK2), RP105 and c-Maf. However, the anti-inflammatory actions of IL-4 did not require IL-10 or the kinase activity of RIPK2. While the TLR-homolog, RP105, is likely to negatively regulate LPS responses by monocytes, IL-4 had no effect on cell surface expression of RP105. Additional studies may determine whether c-Maf, a transcription factor which induces IL-10, also regulates the suppression inflammatory cytokine production by IL-4.

This study identified novel candidates induced by IL-4 in LPS-stimulated human monocytes. However, the molecules involved in the regulation by IL-4 of LPS-induced TNFα production were not definitively identified. Further studies may identify the mechanisms by which IL-4 is anti-inflammatory. Ultimately, this research will contribute towards the development of novel therapies for inflammatory disease.

Publication Type: Thesis (PhD)
Murdoch Affiliation: School of Biological Sciences and Biotechnology
Supervisor: Hart, Prue and Prêle, Cecilia
URI: http://researchrepository.murdoch.edu.au/id/eprint/14844
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