Investigation of the intracellular signalling pathway for interleukin-6 gene expression in skeletal muscle

Investigation of the intracellular signalling pathway for interleukin-6 gene expression in skeletal muscle

Chan, S 2007, Investigation of the intracellular signalling pathway for interleukin-6 gene expression in skeletal muscle, PhD Thesis, School of Medical Sciences, RMIT University.

Document type:	Thesis
Collection:	Theses

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Title	Investigation of the intracellular signalling pathway for interleukin-6 gene expression in skeletal muscle
Author(s)	Chan, S
Year	2007
Abstract	It has been recently demonstrated that the cytokine interleukin (IL)-6 is unique among the so called "inflammatory cytokines" in that it can be rapidly produced by and released from contracting skeletal muscle into the circulation in the absence of muscle damage or markers of inflammation. Moreover, previous studies have also indicated that the muscle-derived IL-6 may play an important role in insulin sensitivity and fat metabolism, which may help to explain some of the beneficial effects associated with exercise. Despite the fact that the magnitude of the contraction mediated IL-6 gene expression is often dependent on the mode, intensity and duration of the exercise bout performed, the signalling events that mediate these processes are poorly understood. Accordingly, the central aim of this thesis of work was to identify the signalling pathways for IL-6 gene transcription in co ntracting skeletal muscle. We firstly sought to examine the cellular origin and distribution of IL-6 within the mass of skeletal muscle in response to exercise. Confirming that skeletal myocytes are a source of the exercise-induced elevation in IL-6 in human skeletal muscle by demonstrating that IL-6 mRNA increases intramyocellularly using in situ hybridisation, we next investigated the pattern of cytokine gene expression in response to contraction. Our data revealed that cytokines are not ubiquitously expressed in human skeletal muscle, and the expression of IL-6 and -8 are both influenced by glycogen availability within the contracting muscle. Moreover, a reduction in intramuscular glycogen also led to a marked phosphorylation of the nuclear p38 MAPK, which was then proven to have a critical role in the mRNA induction of IL-6. Importantly, the transcriptional activation of IL-6 in skeletal muscle appeared to be regulated by a NFêB-independent mechanism, and that NFAT inhibition may have a sensitizing effec t on the skeletal muscle to Ca2+ stimulation. In summary, studies from this thesis suggest that contracting skeletal muscle cells actively produces IL-6 via a mechanism that is atypical from those seen during inflammation. It is clear from this series of studies that IL-6 is produced in muscle cells by a unique pathway that involves changes in metabolic and contractile processes, but not inflammatory signalling cascades.
Degree	PhD Thesis
Institution	RMIT University
School, Department or Centre	School of Medical Sciences
Keyword(s)	Cytokines -- Physiological effect Inflammation

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