Prostaglandin E (PGE) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of deficiency on the body core temperature (Tc) and on the PGE concentration in hypothalamus interstitial fluid () and CSF () of lipopolysaccharide (LPS; 100 μg/kg, i.p.)-treated mice of both sexes. mice did not develop a febrile response. was increased in and mice, and of mice was well maintained at 5 h after LPS injection (1160 pg/ml) compared with mice (316 pg/ml). A microdialysis study revealed that peaked at 2 h after LPS injection in mice (841 pg/ml), whereas the increase in was negligible in mice. The PGE plasma concentration in mice (201 pg/ml) was significantly higher than that in mice (54 pg/ml) at 1 h after LPS injection, whereas the two groups showed similar PGE concentrations in the hypothalamus. Strong Oatp2a1 immunoreactivity was observed in F4/80-positive microglia and perivascular cells and in brain capillary endothelial cells. The changes in Tc and seen in LPS-injected mice were partially attenuated in monocyte-/macrophage-specific (/) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of , possibly by regulating PGE secretion from F4/80-positive glial cells and/or facilitating PGE transport across the blood-brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation. Fever is a physiological response caused by pyrogen-induced release of prostaglandin E (PGE) in the hypothalamus, which plays a central role in regulating the set-point of body temperature. However, it is unclear whether the prostaglandin transporter OATP2A1/ is involved in this response. We show here that LPS-induced fever is associated with increased PGE concentration in hypothalamus interstitial fluid (), but not in CSF (), by means of a microdialysis study in global -knock-out mice and monocyte-/macrophage-specific-knock-out mice. The results suggest that OATP2A1 serves as a regulator of in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells and, therefore, may also play a role in PGE transport across the blood-brain barrier.

Prostaglandin E2 (PGE2) is associated with proliferation and angiogenesis in colorectal tumours. The role of prostaglandin transporter OATP2A1/SLCO2A1 in colon cancer tumorogenesis is unknown. We evaluated mice of various Slco2a1 genotypes in a murine model of colon cancer, the adenomatous polyposis (APC) mutant (Apc ∆716/+) model. Median lifespan was significantly extended from 19 weeks in Slco2a1 +/+/Apc Δ716/+ mice to 25 weeks in Slco2a1 −/−/Apc Δ716/+ mice. Survival was directly related to a reduction in the number of large polyps in the Slco2a1 −/− /Apc ∆716/+ compared to the Slco2a1 +/+/Apc Δ716/+ or Slco2a1 +/−/Apc Δ716/+mice. The large polyps from the Slco2a1 −/− /Apc ∆716/+ mice had significant reductions in microvascular density, consistent with the high expression of Slco2a1 in the tumour-associated vascular endothelial cells. Chemical suppression of OATP2A1 function significantly reduced tube formation and wound-healing activity of PGE2 in human vascular endothelial cells (HUVECs) although the amount of extracellular PGE2 was not affected by an OATP2A1 inhibitor. Further an in vivo model of angiogenesis, showed a significant reduction of haemoglobin content (54.2%) in sponges implanted into Slco2a1 −/−, compared to wildtype mice. These studies indicate that OATP2A1 is likely to promote tumorogenesis by PGE2 uptake into the endothelial cells, suggesting that blockade of OATP2A1 is an additional pharmacologic strategy to improve colon cancer outcomes.

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