Negative feedback of inflammation of macrophages: transcriptional cross-talk of the LPS and IL-10 signalling pathways

Ridley, Michael Luke (2017). Negative feedback of inflammation of macrophages: transcriptional cross-talk of the LPS and IL-10 signalling pathways. University of Birmingham. Ph.D.

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Abstract

The classical picture of interleukin 10 (IL-10) is of a powerful anti-inflammatory cytokine, which suppresses many functions of myeloid cells, including antigen presentation and pro-inflammatory cytokine expression. IL-10 acts via the Janus-activated kinase JAK1 to activate the transcription factor STAT3. The actions of IL-10 are essential for prevention of excessive inflammatory responses, particularly in gut tissues that are constantly exposed to potential pathogens. Many of the antiinflammatory effects of IL-10 have been attributed to the inhibition of the transcription NF-KB.
However, this simplistic picture of IL-10 is becoming increasingly under challenge, with emerging evidence of immune-stimulatory properties, and actions that cannot be attributed to NF-KB inhibition. In this thesis I used monocyte-derived macrophages from healthy human donors to
investigate the effects of IL-10 on responses to LPS and subsequently dissected the molecular mechanisms of these changes in gene expression using small chemical inhibitors and siRNA. These shed new light on the mechanisms by which IL-10 inhibits pro-inflammatory gene expression. They also indicate surprisingly broad and powerful gene-specific cooperative interactions between LPS-induced and IL-10 induced signalling pathways, which are likely to contribute to the subtle immunemodulatory
properties of IL-10.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):