The heterodimeric transcription factor Hypoxia inducible factor-1 (HIF-1) is the key regulator of hypoxia-induced gene expression.

It consists of the constitutive HIF-1b- and the oxygen-sensitive HIF-1a- subunit. Apart from hypoxia several other stimuli are known to induce HIF-1. Inflammatory cytokines as well as reactive oxygen species (ROS) have been shown to increase HIF-1a accumulation and HIF-1 activation in different cell types. Neutrophils are capable of both ROS and cytokine production therefore we established a coculture model to distinguish between the role of ROS and the role of inflammatory cytokines in inflammation induced HIF-1 activation. Wilde type peripheral blood leukocytes (PLB wt) and peripheral blood leukocytes lacking the gp91phox subunit of the NADPH oxidase (PLB-XGD) were stimulated with PMA and fMLP. ROS production was increased only in the PLBwt cells. Coculture of hepatoma cells with stimulated PLBwt resulted in a marked accumulation of HIF-1a which was less prominent when hepatoma cells were cocultured with stimulated PLB-XGD cells. With respect to cytokine expression no significant differences between PLBwt and PLB-XGD were observed. These results indicate that the HIF-1a stabilizing effect can be attributed in part to ROS produced by leukocytes at the site of inflammation.