Mature monocytes migrate selleck inhibitor towards sites of inflammation and infection where they differentiate into inflammatory macrophages or into dendritic cells. Macrophages have the highest phagocytic potential of cells in the area of inflammation. They also present the antigen components previously processed via the major histocompatibility complex II and, via cyto kines, attract other macrophages, granulocytes and T cells into inflamed areas. Monocytes and macrophages require energy in the form of adenosine triphosphate in order to facili tate motion, activa tion and effector functions. Under aerobic conditions, the energy supply of the cells occurs via oxi dative phosphorylation and glycolysis. In the absence of oxygen, OxPhos Inhibitors,Modulators,Libraries does not occur and only glycolysis remains for ATP production, because this process does not require oxygen.

Hypoxia occurs in joint inflammation such as during the pathogenesis of rheumatoid arthritis, Inhibitors,Modulators,Libraries fracture hematomas, and malignant tumors. Ng et al. demonstrated in recent in vivo studies that an inverse correlation exists between synovial oxygen partial pres sure and inflammatory activity in patients with arthritis, the stronger the inflammation, the more pronounced the local hypoxia. Kennedy et al. showed anti TNF therapy, widely used to treat RA, increases the oxygen partial pressure in the joint. For the initial inflammatory envir onment in an early fracture hematoma, the specific cyto kine pattern and typical gene signatures in immune cells reflect a situation of local hypoxia. In addition, Vaupel et al.

showed the important role of hypoxia and hypoxia inducible factors in tumorigenesis. Inhibitors,Modulators,Libraries During monocytopoiesis, monocyte precursor cells in the bone marrow, monocytes in the blood and macro phages in the tissue are subjected to very different oxy gen levels. For example, an oxygen partial pressure of 10 mmHg is present in the Inhibitors,Modulators,Libraries bone marrow of mice. In contrast, much higher pO2 values of 50 to 100 mmHg in the periph eral blood and of 20 to 50 mmHg in healthy tissue were measured. Further more, in inflamed areas macrophages face pathophysio logical hypoxia. In these regions, the oxygen content is lower than in healthy tissues because of imbalance between provision and consumption of oxygen. Dis turbed blood Inhibitors,Modulators,Libraries circulation and inflammatory swellings resulting in a lengthening of the diffusion distance decrease the oxygen supply whereas the influx of meta bolically active immune cells strongly increases the oxy gen consumption.

For these reasons, cells are forced to adapt immediately to the reduced pO2 levels when entering sellekchem these low oxygenated areas. The mechan ism of this adaptation and the temporal relationship of this response to activation and migration are not yet fully understood. Rapid adaptation of monocytes to hypoxia may involve HIF or other factors.