title: Substance P enhances tissue factor release from granulocyte-macrophage colony-stimulating factor-dependent macrophages via the p22phox/β-arrestin 2/Rho A signaling pathway.
abstract: Granulocyte-macrophage colony stimulating factor (GM-CSF) induces procoagulant activity of macrophages. Tissue factor (TF) is a membrane-bound glycoprotein and substance P (SP) is a pro-inflammatory neuropeptide involved in the formation of membrane blebs. This study investigated the role of SP in TF release by GM-CSF-dependent macrophages. SP significantly decreased TF levels in whole-cell lysates of GM-CSF-dependent macrophages. TF was detected in the culture supernatant by enzyme-linked immunosorbent assay after stimulation of macrophages by SP. Aprepitant (an SP/neurokinin 1 receptor antagonist) reduced TF release from macrophages stimulated with SP. Pretreatment of macrophages with a radical scavenger(pyrrolidinedithiocarbamate) also limited the decrease of TF in whole-cell lysates after stimulation with SP. A protein kinase C inhibitor (rottlerin) partially blocked this macrophage response to SP, while it was significantly inhibited by a ROCK inhibitor (Y-27632) or a dynamin inhibitor (dinasore). An Akt inhibitor (perifosine) also partially blocked this response. Furthermore, siRNA targeting p22phox, β-arrestin 2, or Rho A, blunted the release of TF from macrophages stimulated with SP. In other experiments, visceral adipocytes derived from cryopreserved preadipocytes were found to produce SP. In conclusion, SP enhances the release of TF from macrophages via the p22phox/β-arrestin 2/Rho A signaling pathway.
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan; Graduate School of Medical Science, Kumamoto University Medical School, Kumamoto, Japan.
authors: Rui
authors: R
authors: Yamaguchi
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Takatoshi
authors: T
authors: Yamamoto
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Arisa
authors: A
authors: Sakamoto
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Yasuji
authors: Y
authors: Ishimaru
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Shinji
authors: S
authors: Narahara
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Hiroyuki
authors: H
authors: Sugiuchi
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Yasuo
authors: Y
authors: Yamaguchi
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000077608:Aprepitant; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000096:biosynthesis / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000605254:ARRB2 protein, human; D000098:Acetophenones; D000577:Amides; D019390:Arrestins; D001578:Benzopyrans; D016166:Free Radical Scavengers; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013859:Thiocarbamates; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D010767:Phosphorylcholine; C108830:Y 27632; D000077608:Aprepitant; C020972:pyrrolidine dithiocarbamic acid; C105905:perifosine; D013373:Substance P; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013925:Thromboplastin; C085746:rottlerin; D019255:NADPH Oxidases; C086986:CYBA protein, human; D054460:rho-Associated Kinases; D034281:Dynamins
keywords: Granulocyte-macrophage colony-stimulating factor; Neurokinin 1 receptor; Substance P; Tissue factor