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Originally published online as doi:10.1189/jlb.1008644 on July 6, 2009

Published online before print July 6, 2009
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(Journal of Leukocyte Biology. 2009;86:645-653.)
© 2009 Society for Leukocyte Biology

Nucleophosmin may act as an alarmin: implications for severe sepsis

Yuko Nawa*, Ko-ichi Kawahara*, Salunya Tancharoen{dagger}, Xiaojie Meng*, Hisayo Sameshima*, Takashi Ito*, Yoshiki Masuda{ddagger}, Hitoshi Imaizumi{ddagger}, Teruto Hashiguchi* and Ikuro Maruyama*,1

* Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan;
{dagger} Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand; and
{ddagger} Department of Traumatology and Critical Care Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

1. Correspondence: Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: rinken{at}m3.kufm.kagoshima-u.ac.jp

ABSTRACT

NPM is a major nucleolar multifunctional protein involved in ribosome biogenesis, centrosome duplication, cell-cycle progression, apoptosis, cell differentiation, and sensing cellular stress. Alarmins are endogenous molecules released from activated cells and/or dying cells, which activate the immune system and cause severe damage to cells and tissue organs. In the present work, stimulation of cells with the alarmin-inducible molecule endotoxin, for 16 h, resulted in NPM release into the culture supernatants of RAW264.7 cells, a murine macrophage cell line. Extracellular NPM was detected in the ascites of the CLP model. NPM was translocated into the cytoplasm from the nucleus in LPS -stimulated RAW264.7 cells; furthermore, NPM was detected in the cytosols of infiltrated macrophages in the CLP model. rNPM induced release of proinflammatory cytokines, TNF-{alpha}, IL-6, and MCP-1, from RAW264.7 cells and increased the expression level of ICAM-1 in HUVECs. NPM induced the phosphorylation of MAPKs in RAW264.7 cells. Our data indicate that NPM may have potent biological activities that contribute to systemic inflammation. Further investigations of the role of NPM may lead to new therapies for patients with septic shock or other inflammatory diseases.

Key Words: systemic inflammation • sepsis • macrophages