Nucleophosmin may act as an alarmin: implications for severe sepsis.
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.
Nawa
Yuko
Y
Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
Kawahara
Ko-ichi
K
Tancharoen
Salunya
S
Meng
Xiaojie
X
Sameshima
Hisayo
H
Ito
Takashi
T
Masuda
Yoshiki
Y
Imaizumi
Hitoshi
H
Hashiguchi
Teruto
T
Maruyama
Ikuro
I
D000818:Animals; D001201:Ascites / Q000209:etiology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005562:Formazans / Q000378:metabolism; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000302:isolation & purification / Q000378:metabolism*; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism*; D056489:Nucleoplasmins; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors
D016895:Culture Media, Serum-Free; D016207:Cytokines; D005562:Formazans; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D056489:Nucleoplasmins; D010750:Phosphoproteins; D013778:Tetrazolium Salts; C079782:MTT formazan