Interleukin-25 Expressed by Brain Capillary Endothelial Cells Maintains Blood-Brain Barrier Function in a Protein Kinase Cϵ-dependent Manner

Kunio Kataoka,Tetsuya Mizuno,Yoshifumi Sonobe,Akio Suzumura,Hua Li,Takashi Kanda,Maya Mimuro,Yoshio Hashizume,Yasuteru Sano,Shijie Jin,Hideyuki Takeuchi

doi:10.1074/jbc.m109.025940

Abstract

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.

Highlights

Interleukin (IL)-25, a member of the IL-17 family of cytokines, is expressed in the brains of normal mice
IL-25 is known to induce Th2 responses and to be produced by cells related to allergic responses such as Th2 cells, mast cells, and lung macrophages stimulated with anti-CD3/CD28, IgE, and allergens [1, 3, 4]
A previous study indicated that IL-25 mRNA was expressed in the whole brain tissue of normal mice [19], indicating that IL-25 plays a distinct role in the central nervous system

Summary

Introduction

Interleukin (IL)-25, a member of the IL-17 family of cytokines, is expressed in the brains of normal mice. IL-25 restores the reduced expression of tight junction proteins, occludin, junction adhesion molecule, and claudin-5, induced by TNF-␣ in BCECs and repairs TNF-␣-induced blood-brain barrier (BBB) permeability. Forster et al [14] demonstrated that TNF-␣ had an inhibitory effect on occludin and claudin-5 expression in human brain capillary endothelial cells (BCECs).

Results

Conclusion