Differential Control of Immune Cell Function by HIF-1 Signalling Pathway

Human inflammatory/innate immune responses lie at the core of resistance to infectious disease and determine the nature of pathophysiological reactions of hematopoietic cells like leukaemia and allergy. The crucial step in these events is the ability of immune cells to function properly, which depends on their adaptation to stress caused by pro-inflammatory stimulation. The mechanisms underlying this crucial biochemical dogma, and its role in normal and pathological cross-links between immune cells, are not well understood. This PhD programme was devoted to investigation of these important problems.

We found that the inflammatory mediator interleukin 1 beta (IL-1?), derived from human innate immune cells, triggers production of the major hematopoietic growth factor, the stem cell factor (SCF) in MCF-7 human epithelial cells. This process is controlled by the hypoxia-inducible factor 1 (HIF-1) transcription complex, which regulates cellular adaptation to inflammatory/hypoxic stress by promoting angiogenesis and glycolytic degradation of the glucose. Translational mechanism, which is majorly dependent on the mammalian target of rapamycin (mTOR) kinase pathway underlies IL-1?-induced HIF-1 accumulation and also contributes to SCF biosynthesis. The effect is applicable in both in vitro and in vivo systems. Further experiments demonstrated the involvement of this biosynthetic mechanism in the differential control of normal and pathological functions of inflammatory cells including monocytes, basophils and mast cells. Our results also demonstrated possible biochemical mechanisms regarding the cross-talk between inflammation and SCF-dependent blood cancer (leukaemia), which remains a serious medical burden worldwide. Finally, the pathways investigated could be further considered as potential therapeutic targets for pharmacological correction of human inflammatory reactions and treating cancer/leukaemia by classic and principally novel approaches, such as utilisation of gold nanoparticles.