Transforming growth factor- (TGF-), a pleiotropic cytokine, regulates cell proliferation, differentiation and apoptosis, and plays a key role in development and tissue homeostasis. TGF- functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions as well as the production of pro-inflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF- induces fever like that produced by pro-inflammatory cytokines. In this study, we investigated the mechanism of TGF--induced fever. The intracisternal administration of TGF- increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2) selective inhibitor significantly suppressed TGF--induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF- is COX-2 and PGE2 dependent. TGF- increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF- receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF- receptor), suggesting that TGF- directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF- as a pro-inflammatory cytokine in the central nervous system.