Sites of bacterial inflammation recruit leukocytes from relatively normoxic vessels into highly hypoxic areas. Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor that adapts cellular responses to decreasing levels of oxygen tension. We have previously shown that the crucial HIF-1a subunit can also be induced by bacterial lipopolysaccharides (LPS) and that the establishment of endotoxin tolerance also affects the HIF-system mimicking a functional knock down of HIF-1a.

In our work, we tried to characterise the role of HIF-1a in monocyte-endothelial interaction for the extravasation of monocytes starting from monocyte adhesion, diapedesis and trafficking to the site of infection. Experiments were performed with human monocytes (THP-1) and human umbilical vein cord endothelial cells (HUVEC) under normoxic and hypoxic conditions.

Endotoxin-tolerant THP-1 cells show significantly reduced extravasation into extracellular matrix although adhesion proteins such as ICAM-1 are upregulated. Extravasated tolerant monocytes are significantly reduced in viability under hypoxic conditions due to down regulated levels of HIF-1a protein and mRNA. We were also able to establish endotoxin tolerance in freshly isolated HUVEC showing significantly lower levels of HIF-1a protein and mRNA levels. In contrast to monocytes, protein expression of ICAM-1 did not change in tolerant endothelial cells compared to the controls.

Taken together, the establishment of endotoxin tolerance in both monocytic and endothelial cells leads to severe consequences on monocyte-endothelial interaction, probably by getting monocytes stick deeply to the endothelium. Thus, only a small number of monocytes can be attracted to sites of bacterial inflammation showing a rather low potential to adapt to the hypoxic environment. This may lead to an almost complete loss of function of the adaptive immune response.