title: 16-kDa prolactin down-regulates inducible nitric oxide synthase expression through inhibition of the signal transducer and activator of transcription 1/IFN regulatory factor-1 pathway.
abstract: Angiogenesis plays a key role in promoting tumorigenesis and metastasis. Several antiangiogenic factors have been shown to inhibit tumor growth in animal models. Understanding their mechanism of action would allow for better therapeutic application. 16-kDa prolactin (PRL), a NH2-terminal natural breakdown fragment of the intact 23-kDa PRL, exerts potent antiangiogenic and antitumor activities. The signaling mechanism involved in 16-kDa PRL action in endothelial cells remains unclear. One of the actions of 16-kDa PRL is to attenuate the production of nitric oxide (NO) through the inhibition of inducible NO synthase (iNOS) expression in endothelial cells. To delineate the signaling mechanism from 16-kDa PRL, we examined the effect of 16-kDa PRL on interleukin IL-1beta-inducible iNOS expression, which is regulated by two parallel pathways, one involving IFN regulatory factor 1 (IRF-1) and the other nuclear factor-kappaB (NF-kappaB). Our studies showed that 16-kDa PRL specifically blocked IRF-1 but not NF-kappaB signaling to the iNOS promoter. We found that IL-1beta regulated IRF-1 gene expression through stimulation of p38 mitogen-activated protein kinase (MAPK), which mediated signal transducer and activator of transcription 1 (Stat1) serine phosphorylation and Stat1 nuclear translocation to activate the IRF-1 promoter. 16-kDa PRL effectively inhibited IL-1beta-inducible p38 MAPK phosphorylation, resulting in blocking Stat1 serine phosphorylation, its subsequent nuclear translocation and activation of the Stat1 target gene IRF-1. Thus, 16-kDa PRL inhibits the p38 MAPK/Stat1/IRF-1 pathway to attenuate iNOS/NO production in endothelial cells.
authors.affiliation: Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sok-Hyong
authors.initials: SH
authors.lastname: Lee
authors.forename: Michiya
authors.initials: M
authors.lastname: Nishino
authors.forename: Tuhina
authors.initials: T
authors.lastname: Mazumdar
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
authors.forename: Matthew
authors.initials: M
authors.lastname: Galfione
authors.forename: Florence L
authors.initials: FL
authors.lastname: Lee
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Lee
authors.forename: Albert
authors.initials: A
authors.lastname: Liang
authors.forename: Jeri
authors.initials: J
authors.lastname: Kim
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011388:Prolactin / Q000494:pharmacology*; D051381:Rats; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; C494259:Irf1 protein, rat; D016328:NF-kappa B; D010446:Peptide Fragments; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators; D009569:Nitric Oxide; D011388:Prolactin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases