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Effects of tumour hypoxia on DC differentiation and maturation

preclinical study dataset

We investigated the effects of tumour hypoxia on DC differentiation and maturation and gathered data in mice.

This is a an important topic as sites of inflammation are often characterized by both low oxygen tension and an extensive infiltration of inflammatory leukocytes, including DC, which need to move against oxygen gradients. We showed that oxygen availability is necessary to promote full monocyte-derived DC differentiation and maturation. Low oxygen tension (hypoxia) inhibits expression of several differentiation and maturation markers (CD1a, CD40, CD80, CD83, CD86, and MHC class II molecules) in response to lipopolysaccharide (LPS), as well as their stimulatory capacity for T-cell functions. These events are paralleled by impaired up-regulation of the chemokine receptor CCR7, an otherwise necessary event for the homing of mature DCs to lymph nodes. In contrast, hypoxia strongly up-regulates production of proinflammatory cytokines, particularly TNFalpha and IL-1beta, as well as the inflammatory chemokine receptor CCR5. Subcutaneous injection of hypoxic DCs into the footpads of mice results in defective DC homing to draining lymph nodes, but enhanced leukocyte recruitment at the site of injection. Thus, hypoxia uncouples the promotion of inflammatory and tissue repair from sentinel functions in DCs, which we suggest is a safeguard mechanism against immune reactivity to damaged tissues.

During the next period we wish to characterize the molecular basis of our observations. In particular, an effort will be made to investigate mechanisms underlying the enhanced inflammatory functions of differentiating DC in hypoxia.

Biochemical and functional studies will be focused on the role of the Hypoxia- Inducible Factor-1 and -2, (HIF-1 and HIF-2) as they represent putative mediators of the adaptive response of DC to hypoxia.






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