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 NH 2 -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-1B-inducible iNOS expression, which is regulated by two parallel pathways, one involving IFN regulatory factor 1 (IRF-1) and the other nuclear factor-KB (NF-KB). Our studies showed that 16-kDa PRL specifically blocked IRF-1 but not NF-KB signaling to the iNOS promoter. We found that IL-1B 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-1B-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. (Cancer Res 2005; 65(17): 7984-92)

On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

“…However, both cytokines used here may activate JAK/STAT pathways. TNFα activates JAK/STAT1 [42] and IL1β activates STAT1 [43] and a STAT-like factor, leading to activation of gene transcription [44]. Therefore our observations are compatible with a pathway inducing transcriptional activation of CH25H identified in dendritic cells and macrophages [4].…”

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

“…The antiangiogenic effect was mainly due to apoptosis of both murine-and tumour-derived endothelial cells, reflecting previous findings in IFN-g-transfected brain tumour cells (Fathallah-Shaykh et al, 2000). The p38 MAPK/Stat1/IRF-1 pathway (Wang et al, 1999;Huang et al, 2002;Lee et al, 2005), cathepsin B (Li and Pober, 2005), Fas/FasL interaction (Li et al, 2002), integrin function (Ruegg et al, 1998) and NO production (Yamaoka et al, 2002;Vekemans et al, 2004;Lee et al, 2005) have been shown to drive IFN-g-dependent apoptosis of endothelial cells. As not only human but also murine endothelial cells in ACN/IFN-g xenografts were TUNEL-positive, neither the released human IFN-g nor other species-specific mediators could be involved in mediating apoptosis in our model.…”

Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin

“…16K-PRL blocks a variety of endothelial cell functions (Corbacho et al, 2002;Gonzalez et al, 2004;Lee et al, 2005) and inhibits angiogenesis in ocular tissues (Dueñas et al, 1999;Pan et al, 2004;Aranda et al, 2005) and in tumors (Bentzien et al, 2001;Kim et al, 2003). The specific enzymes responsible for generating 16K-PRL are largely unknown.…”