Intracisternal administration of transforming growth factor-beta evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells.
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-beta-induced fever. The intracisternal administration of TGF-beta increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-beta-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE(2) synthesis pathway, suggesting that fever induced by TGF-beta is COX-2 and PGE(2) dependent. TGF-beta increased PGE(2) 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-beta receptor, some COX-2-immunoreactive 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.
Matsumura
Shigenobu
S
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Shibakusa
Tetsuro
T
Fujikawa
Teppei
T
Yamada
Hiroyuki
H
Matsumura
Kiyoshi
K
Inoue
Kazuo
K
Fushiki
Tohru
T
D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004790:Enzyme Induction; D005334:Fever / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000502:physiology*
C526764:Acvrl1 protein, rat; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; D029404:Activin Receptors; D015232:Dinoprostone