Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis.
BLT2 is a low-affinity leukotriene B(4) (LTB(4)) receptor that is activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB(4). Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. To clarify the role of BLT receptors in intestinal inflammation, we assessed susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice lacking either BLT1 or BLT2. BLT2(-/-) mice exhibited increased sensitivity to DSS as compared to wild-type and BLT1(-/-) mice, with more severe body weight loss and inflammation. Expression of inflammatory cytokines such as interferon (IFN)-γ, interleukin (IL)-1β, and IL-6, chemokines such as CXC chemokine ligand 9 (CXCL9) and C-C motif chemokine 19 (CCL19), and metalloproteinases was highly up-regulated in the colons of DSS-treated BLT2(-/-) mice, and there was an enhanced accumulation of activated macrophages. Phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was also markedly accelerated in the crypts of DSS-treated BLT2(-/-) mice. Madin-Darby canine kidney II (MDCKII) cells transfected with BLT2 exhibited enhanced barrier function as measured by transepithelial electrical resistance (TER) and FITC-dextran leakage through MDCK monolayers. Thus, BLT2 is expressed in colon cryptic cells and appears to protect against DSS-induced colitis, possibly by enhancing barrier function in epithelial cells of the colon. These novel results suggest a direct anti-inflammatory role of BLT2 that is distinct from the proinflammatory roles of BLT1.
Iizuka
Yoshiko
Y
Department of Medical Biochemistry, Graduate School of Medical Sciences, The University of Tokyo, Tokyo, Japan.
Okuno
Toshiaki
T
Saeki
Kazuko
K
Uozaki
Hiroshi
H
Okada
Shinji
S
Misaka
Takumi
T
Sato
Tetsuya
T
Toh
Hiroyuki
H
Fukayama
Masashi
M
Takeda
Naoki
N
Kita
Yoshihiro
Y
Shimizu
Takao
T
Nakamura
Motonao
M
Yokomizo
Takehiko
T
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004285:Dogs; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; C503704:Ltb4r1 protein, mouse; C412867:Ltb4r2 protein, mouse; D018102:Receptors, Leukotriene B4; D007371:Interferon-gamma; D016264:Dextran Sulfate