The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells.
Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell-deficient WBB6F(1)-W/W(v) mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F(1)-W/W(v) mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca(2+) mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell-mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell-mediated inflammatory diseases.
Moriyama
Maiko
M
Department of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, 839-0864, Japan. moriyama@Isi.kurume-u.ac.jp
Sato
Takahiro
T
Inoue
Hiromasa
H
Fukuyama
Satoru
S
Teranishi
Hitoshi
H
Kangawa
Kenji
K
Kano
Tatsuhiko
T
Yoshimura
Akihiko
A
Kojima
Masayasu
M
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007279:Injections, Subcutaneous; D008214:Lymphocytes / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009479:Neuropeptides / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology
D008565:Membrane Proteins; D009479:Neuropeptides; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; D005620:Freund's Adjuvant