The role of gp130 receptor signalling in inflammation and metabolism

Upon exercise Interleukin-6 (IL-6) is released by contracting skeletal muscle. This increased release of this cytokine increases fat and glucose oxidative metabolism within muscle and adipose and suppress hepatic glucose output. IL-6 is an unsuitable anti-obesity therapeutic agent as it is implicated in the pathogenesis of many inflammatory conditions. Classic IL-6 signal transduction occurs through a trans-membrane complex consisting of an IL-6 receptor α homo-dimer and gp130 receptor-β (gp130Rβ). Alternatively, signalling may occur through a complex of IL-6 and its soluble receptor (sIL-6R) which in turn targets membrane bound gp130Rβ. This phenomenon known as “IL-6 trans-signalling” has implications, as cells devoid of the membrane bound IL-6 receptor remain responsive to the cytokine due to the ubiquitous expression of gp130. Futhermore, it is known that the pro inflammatory effects of IL-6 are mostly mediated via IL-6 trans-signalling. Interestingly, in transgenic mice over expressing a soluble form of gp130 (sgp130), the naturally occurring competitive inhibitor of sIL-6R signalling, inflammation is prevented. Thereby, co-treatment with IL-6 and sgp130 may have therapeutic advantages for obesity related diseases, providing signalling exclusively through the membrane bound IL-6Rα/gp130β.

The primary focus of this dissertation was to examine the effect of IL-6/sIL-6R signalling in the presence and absence of sgp130 on inflammation and metabolism within skeletal muscle, adipose and liver in vitro and in vivo. Hyper IL-6, a designer cytokine consisting of rh-IL-6 and sIL-6R connected via a polypeptide linker, was utilised to mimic IL-6 trans-signalling. In vitro, phosphorylation of STAT3 (Tyr705), and Akt (Ser473) were elevated in both L6 myotubes and CRL1439 hepatocytes incubated with Hyper IL-6 when compared with control. Importantly, signalling was reduced upon co-treatment with sgp130Fc in CRL1439 whilst it was entirely preserved in myotubes. Moreover, Hyper IL-6 potentiated Insulin stimulated glucose uptake in the absence and presence of sgp130Fc.

Consistent with the fore mentioned data, IL-6 trans-signalling events occured in liver, muscle and epidydimal White Adipose Tissue (WAT) in vivo, in a tissue type dependent manner. Moreover, it was demonstrated sgp130Fc inhibited Hyper IL-6 induced signalling, however the degree to which inhibition occurred was tissue type dependent.

Finally, contrary to the transient release seen during exercise, states of disease are often associated with chronically elevated IL-6 within the circulation leading to aberrant pathway activation and inflammation within many tissues. As this paradox exists, prolonged Hyper IL-6 administration on inflammation and whole body energy metabolism was examined in vivo. Although sgp130Fc was able to prevent severe injury and chronic inflammation in the liver as a consequence of prolonged Hyper IL-6 treatment, it was unable to improve insulin resistance induced by this cytokine. This could reflect the enhanced bioactivity of the designer cytokine.

Collectively, these data support the proposition that in muscle, Hyper IL-6 induced trans-signalling is neutralised by sgp130Fc whilst the beneficial effects on metabolism associated with membrane bound signalling remains intact in vitro. In vivo, acute administration of this designer cytokine is able to regulate signalling pathways associated with metabolism and inflammation, an effect that sgp130Fc co-administration inhibited in a tissue type dependent manner. Due to the potency of Hyper IL-6, even when co-administered sgp130FC, it remains a poor candidate as a therapeutic tool in the war against obesity. This, however, does not discount the potential of a gp130 receptor/ligand like drug design as an anti-obesity agent.