Title:
Roles of leukotriene B4 receptors in inflammation and immunity

Takehiko Yokomizo, M.D., Ph.D., Professor
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University
CREST of JST

Abstract:
Leukotriene B4 (LTB4) is known as a lipid-derived classic chemoattractant for granulocytes. I cloned and characterized two G-protein coupled receptors (GPCRs) for LTB4, BLT1 (1) and BLT2 (2). BLT1 is a high-affinity GPCR for LTB4, and potentiates inflammatory and immunological reactions by activating granulocytes, macrophages (3), dendritic cells (4), differentiated T cells (5) and osteoclasts (6). BLT2 was originally identified as a low-affinity LTB4 receptor (2), and we recently purified its intrinsic ligand from tissue lipid extracts and identified it as 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT). Synthetic 12-HHT bound and activated BLT2 at lower concentrations than LTB4 in ligand binding, GTP g S binding, and calcium mobilization assays (7). 12-HHT has been known as a by-product of thromboxane A2 biosynthesis, however, its biological functions have not been clarified. Interestingly, BLT2-deficient mice are more susceptible for dextran-sodium sulfate (DSS)-induced colitis, and this was due to the loss of BLT2-dependent barrier function in colon epithelium (8). Thus, BLT1 is a pro-inflammatory and BLT2 is an anti-inflammatory receptor. I will discuss the roles of these receptors in vivo, showing phenotypes of mice deficient in either of BLT1 or BLT2 in several inflammatory and immunological disease models.

References:
Yokomizo, Nature (1997) 387, p620-624

Yokomizo, J. Exp. Med. (2000) 192, p421-432

Toda, Biochimie (2010) 96, p682-691

Okamoto, J. Biol. Chem. In press

Terawaki, J. Immunol. (2005) 175, p4217-4225

Hikiji, PNAS (2010) 106, p21294-21299

Okuno, J. Exp. Med. (2008) 205, p759-766

Iizuka, FASEB J. In press