DIFFERENTIAL EFFECTS OF IL-6-TYPE CYTOKINES, THEIR INTERPLAY WITH HYPOXIA AND RESULTING EFFECTS ON THE METABOLISM

IL-6-type cytokines signal mainly via the Jak/STAT pathway using the common receptor chain gp130. They are implicated in various biological processes such as differentiation, apoptosis, tissue regeneration and proliferation. However, one of their main functions is the regulation of inflammatory processes, especially the initial induction of an inflammatory response. They hereby exert key steps in the onset as well as in the termination of an inflammation and in the promotion of the shift from the innate to the adaptive immune response. In hepatocellular carcinoma (HCC) IL-6 has been identified as a key factor in the onset as well as in the progression of this cancer.
In this study we first investigated the effects of the IL-6-type cytokine IL-27 on hepatic cells. By evaluating IL-27 signalling in several HCC cell lines as well as hepatic cells, we could demonstrate that IL-27 does, in contrary to other IL-6-type cytokines, activate STAT1 and STAT3. A transcriptional and protein read-out of STAT3 was not found in hepatic cells. Thus, IL-27 exerts interferon γ-like functions only in the liver. Interestingly, we could further show that the IL-27 signalling can still be repressed by the canonical IL-6-type cytokine feedback regulator SOCS3, following a pre-stimulation with other IL-6-type cytokines.
The second part of this thesis focused on the effects of the IL-6-type cytokine Oncostatin M (OSM) on the cellular metabolism. We hereby evaluated to which extent OSM-mediated STAT3 activation can induce a Warburg-like, highly glycolytic, metabolic phenotype under normoxia. OSM induced the expression of HIF-1α, a key factor mediating the shift to a highly glycolytic phenotype, in several HCC cell lines and immortalized hepatocytes.
In the non-neoplastic hepatocyte cell line, PH5CH8, this led to the induction of a more glycolytic metabolic phenotype. The observed changes in these immortalized hepatocytes did not fully resemble the metabolic state seen under hypoxia, since mainly the observed induction of PDK1 seems to explain the effect. Overall we could not observe strong effects on glycolytic enzymes or other canonical HIF-1α target genes involved in metabolism, on a transcriptional or protein expression level in the investigated cells.
Interestingly we found that HIF-1α does not seem to be mediating all the early adaptions of the cellular metabolism to hypoxia. The early inhibition of the pyruvate dehydrogenase complex could be shown to be independent of the HIF-1α-mediated up-regulation of the pyruvate dehydrogenase kinase 1, but might rather be induced by reactive oxygen species, created during the switch from normoxia to hypoxia.

In summary we could show that in the liver IL-27 exerts interferon γ-like effects. Additionally, cytokine-activated STAT3 does not per se induce a glycolytic metabolic phenotype and HIF-1α is not necessary for some of the early adaptions of the cellular metabolism to hypoxia.