Intracisternal administration of transforming growth factor-beta evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

摘要

First published October 24, 2007; doi:10.1J52/ajpregu.00181.2007.-Transforming growth factor-beta (TGF-beta), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-beta functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-beta induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF--induced fever. The intracisternal administration of TGF-beta increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-seIective inhibitor significantly suppressed TGF-beta-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-beta is COX-2 and PGE2 dependent. TGF-beta 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-immu-noreactive cells express TGF-beta receptor, some COX-2-immunoreac-tive cells express activin receptor-like kinase~(-1) (ALK~(-1), an endothelial cell-specific TGF-beta receptor), suggesting that TGF-beta directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-beta as a proinflammatory cytokine in the central nervous system.