Association of reduced heme oxygenase-1 with excessive Toll-like receptor 4 expression in peripheral blood mononuclear cells in Behçet's disease.
BACKGROUND
Toll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet's disease.


METHODS
Thirty-three patients with Behçet's disease and 30 healthy control individuals were included in the study. Expression levels of HO-1, TLR2 and TLR4 mRNA were semiquantitatively analyzed using a real-time PCR technique, and HO-1 protein level was determined by immunoblotting in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes. In some experiments, cells were stimulated with lipopolysaccharide or heat shock protein-60; these proteins are known to be ligands for TLR2 and 4.


RESULTS
Levels of expression of HO-1 mRNA were significantly reduced in PBMCs from patients with active Behçet's disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity. Moreover, HO-1 expression in PBMCs from patients with Behçet's disease was repressed in the presence of either lipopolysaccharide or heat shock protein-60.


CONCLUSIONS
The results suggest that upregulated TLR4 is associated with HO-1 reduction in PBMCs from patients with Behçet's disease, leading to augmented inflammatory responses.
Kirino
Yohei
Y
Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 236-0004, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan. kirino@yokohama-cu.ac.jp
Takeno
Mitsuhiro
M
Watanabe
Reikou
R
Murakami
Shuji
S
Kobayashi
Masayoshi
M
Ideguchi
Haruko
H
Ihata
Atsushi
A
Ohno
Shigeru
S
Ueda
Atsuhisa
A
Mizuki
Nobuhisa
N
Ishigatsubo
Yoshiaki
Y
D000328:Adult; D001528:Behcet Syndrome / Q000097:blood*; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000494:pharmacology; D003199:Computer Systems; D005260:Female; D051547:Heme Oxygenase-1 / Q000097:blood* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000097:blood*
D018834:Chaperonin 60; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051547:Heme Oxygenase-1