Interleukin-6 Promotes 2-Deoxyglucose Uptake Through p44/42 MAPKs Activation Via Ca2+/PKC and EGF Receptor in Primary Cultured Chicken Hepatocytes

Interleukin-6 (II-6) is involved in a variety of biological responses, including the glucose metabolism and cell growth, which is a critical physiological function requiring multiple metabolic pathways. Therefore, in the present study, we examined the effect of II-6 art 2-deoxyglucose, (2-DG) uptake and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased 2-DG uptake in a time-(4h) and a dose-(5 ng/ml) dependent manner. Indeed, IL-6 increased GLUT-2 mRNA and protein expression as well as 2-DG uptake, which were blocked by actinomycin D (AD, transcription inhibitor) and cycloheximide (CHX, translation inhibitor). IL-6 (10 ng/ml) increased the level of IL-6R alpha and glycoprotein (gp) 130 (IL-6R beta) protein expressions. IL-6 increased Janus Kinase (JAK)-2, signal transducer and activator of transcription (STAT)-3 phosphorylation, intracellular Ca-2 concentration, and PKC phosphorylation. IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression were blocked by JAK2-specific siRNA, a STAT3 inhibitor, staurosporine, and bisindolyimaleimide I (PKC inhibitors). In addition, IL-6 increased EGFR/src/FAK, PI3K/Akt phosphorylation and 2-DG uptake as well as GLUI-2 protein expression, which were blocked by AG 1478 (EGF receptor inhibitor), PP2 (src family of tyrosine kinase inhibitor), PI3K-specific siRNA, and a Akt inhibitor. Furthermore, IL-6 increased p444/42 MAPKs phosphorylation and p44 and p42 MAPK-specific siRNA mixture blocked IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression. In conclusion, IL-6 stimulates the 2-DG uptake through p44/42 MAPKs activation via Ca-2/PKC and EGF receptor in primary cultured chicken hepatocytes.