Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cepsilon-dependent manner.
Interleukin (IL)-25, a member of the IL-17 family of cytokines, is expressed in the brains of normal mice. However, the cellular source of IL-25 and its function in the brain remain to be elucidated. Here, we show that IL-25 plays an important role in preventing infiltration of the inflammatory cells into the central nervous system. Brain capillary endothelial cells (BCECs) express IL-25. However, it is down-regulated by inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, IL-17, interferon-gamma, IL-1beta, and IL-6 in vitro, and is also reduced in active multiple sclerosis (MS) lesions and in the inflamed spinal cord of experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, IL-25 restores the reduced expression of tight junction proteins, occludin, junction adhesion molecule, and claudin-5, induced by TNF-alpha in BCECs and consequently repairs TNF-alpha-induced blood-brain barrier (BBB) permeability. IL-25 induces protein kinase Cepsilon (PKCepsilon) phosphorylation, and up-regulation of claudin-5 is suppressed by PKCepsilon inhibitor peptide in the IL-25-stimulated BCECs. These results suggest that IL-25 is produced by BCECs and protects against inflammatory cytokine-induced excessive BBB collapse through a PKCepsilon-dependent pathway. These novel functions of IL-25 in maintaining BBB integrity may help us understand the pathophysiology of inflammatory brain diseases such as MS.
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, USA. sonobe@riem.nagoya-u.ac.jp
Yoshifumi
Y
Sonobe
Hideyuki
H
Takeuchi
Kunio
K
Kataoka
Hua
H
Li
Shijie
S
Jin
Maya
M
Mimuro
Yoshio
Y
Hashizume
Yasuteru
Y
Sano
Takashi
T
Kanda
Tetsuya
T
Mizuno
Akio
A
Suzumura
D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002463:Cell Membrane Permeability; D042783:Endothelial Cells / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051744:Protein Kinase C-epsilon