Expressions of tight junction proteins Occludin and Claudin-1 are under the circadian control in the mouse large intestine: implications in intestinal permeability and susceptibility to colitis.
OBJECTIVE
The circadian clock drives daily rhythms in behavior and physiology. A recent study suggests that intestinal permeability is also under control of the circadian clock. However, the precise mechanisms remain largely unknown. Because intestinal permeability depends on tight junction (TJ) that regulates the epithelial paracellular pathway, this study investigated whether the circadian clock regulates the expression levels of TJ proteins in the intestine.


METHODS
The expression levels of TJ proteins in the large intestinal epithelium and colonic permeability were analyzed every 4, 6, or 12 hours between wild-type mice and mice with a mutation of a key clock gene Period2 (Per2; mPer2(m/m). In addition, the susceptibility to dextran sodium sulfate (DSS)-induced colitis was compared between wild-type mice and mPer2(m/m) mice.


RESULTS
The mRNA and protein expression levels of Occludin and Claudin-1 exhibited daily variations in the colonic epithelium in wild-type mice, whereas they were constitutively high in mPer2(m/m) mice. Colonic permeability in wild-type mice exhibited daily variations, which was inversely associated with the expression levels of Occludin and Claudin-1 proteins, whereas it was constitutively low in mPer2(m/m) mice. mPer2(m/m) mice were more resistant to the colonic injury induced by DSS than wild-type mice.


CONCLUSIONS
Occludin and Claudin-1 expressions in the large intestine are under the circadian control, which is associated with temporal regulation of colonic permeability and also susceptibility to colitis.
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Oh-oka
OO
Kyoko
The First Department of Surgery, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Hiroshi
H
Kono
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Kayoko
K
Ishimaru
Department of Epigenetic Medicine, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Kunio
K
Miyake
Department of Epigenetic Medicine, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Takeo
T
Kubota
Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Hideoki
H
Ogawa
Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Ko
K
Okumura
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Shigenobu
S
Shibata
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Atsuhito
A
Nakao
D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D062445:Claudin-1 / Q000235:genetics*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics; D024721:E-Box Elements; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D053583:Interleukin-1beta / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007420:Intestine, Large / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin / Q000235:genetics*; D056950:Period Circadian Proteins / Q000378:metabolism; D010539:Permeability; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000737:chemistry; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D056930:ARNTL Transcription Factors; D062445:Claudin-1; D053583:Interleukin-1beta; D062793:Occludin; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D056926:CLOCK Proteins