Neurotensin enhances nitric oxide generation via the JAK2-STAT1 pathway in murine macrophage Raw264.7 cells during costimulation with LPS and IFNgamma.
Neurotensin has been known to be implicated in immune function, but its molecular mechanisms remain largely unclear. In this study, we report that neurotensin increased the intracellular calcium levels of murine macrophage Raw264.7 cells, and that this calcium increase disappeared in the presence of either U73122, a PLC inhibitor, or SR48692, a neurotensin receptor antagonist. Also, the production of nitric oxide (NO) during costimulation with lipopolysaccharide (LPS) and interferon gamma (IFNgamma) was potentiated by exposure to neurotensin, whereas neurotensin itself had no ability to induce NO generation. The up-regulation of NO generation was correlated with the induction of inducible NO synthase (iNOS). In addition, the activities of janus activated kinase 2 (JAK2)-signal transducer and activated transcription 1 (STAT1) and the migration capacity of macrophage were increased as the result of costimulation of neurotensin with LPS and IFNgamma, and pretreatment of either U73122 or SR48692 attenuated these phenomenon. Moreover, the neurotensin-mediated enhancement of NO generation and migration were observed in the wild-type JAK2 transfected cells, but not in the dominant negative JAK2 transfected cells. Together, these results demonstrate that neurotensin can effect enhancement in LPS/IFNgamma-induced NO generation and migration capacity, via the JAK2-STAT1 pathway.
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, San31 Hyoja-Dong, Nam-Gu Pohang, Kyungbuk 790-784, South Korea.
Hyeon Soo
HS
Kim
Sanatombi
S
Yumkham
Jang Hyun
JH
Choi
Sun Hee
SH
Lee
Tae-Ho
TH
Kim
Sung Ho
SH
Ryu
Pann-Ghill
PG
Suh
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004963:Estrenes / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009496:Neurotensin / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004963:Estrenes; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011760:Pyrrolidinones; D011804:Quinolines; D018028:Receptors, Neurotensin; D050794:STAT1 Transcription Factor; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C079087:SR 48692; D009569:Nitric Oxide; D009496:Neurotensin; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053614:Janus Kinase 2; D010738:Type C Phospholipases; D002118:Calcium