| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Ligand and Osteoprotegerin Regulate Proinflammatory Cytokine Production in Mice1
* Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan;
Nagahama Institute for Biochemical Science, Oriental Yeast, Shiga, Japan; and
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
Receptor activator of NF-
B ligand (RANKL) is a membrane-bound or soluble cytokine essential for osteoclast differentiation, whereas the decoy receptor osteoprotegerin (OPG) masks RANKL activity. In mouse serum, both soluble RANKL and OPG are detectable. We observed that mice injected with LPS showed significantly down-regulated serum RANKL levels, whereas serum OPG levels were up-regulated. However, the roles of RANKL and OPG in innate immunity remain obscure. We found that RANKL pretreatment suppressed production of proinflammatory cytokines in macrophages in response to stimulation by bacteria and their components. Furthermore, such RANKL-induced tolerance in macrophages was inhibited by GM-CSF treatment, which blocks RANKL signaling. RANKL-induced tolerance occurred in the absence of c-Fos, which is essential for osteoclast differentiation. In mice lacking OPG, LPS-induced production of proinflammatory cytokines was reduced, whereas in mice lacking RANKL, it was increased, and lethality following LPS injection was also elevated, suggesting that constitutive activities of RANKL suppress cytokine responsiveness to LPS in vivo. Strikingly, prior administration of RANKL protected mice from LPS-induced death. These data reveal prophylactic potential of RANKL in acute inflammatory diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects, and in part by Done Science.
2 Address correspondence and reprint requests to Dr. Koichi Matsuo, Department of Microbiology and Immunology, School of Medicine, Keio University, 160-8582 Tokyo, Japan. E-mail address: matsuo{at}sc.itc.keio.ac.jp
3 Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; OPG, osteoprotegerin; TRAF, TNFR-associated factor; MDBM, M-CSF-dependent bone marrow-derived macrophage; MDSM, M-CSF-dependent spleen-derived macrophage; TRIF, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-
; TRAM, TRIF-related adaptor molecule; IRAK, IL-1R-associated kinase.
This article has been cited by other articles:
|
|
 |
|
  T. Chino, K. E. Draves, and E. A. Clark Regulation of dendritic cell survival and cytokine production by osteoprotegerin J. Leukoc. Biol., October 1, 2009; 86(4): 933 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ferrari-Lacraz and S. Ferrari Effects of RANKL Inhibition on Inflammation and Immunity IBMS BoneKEy, March 1, 2009; 6(3): 116 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. W. Quinn, N. A. Sims, H. Saleh, D. Mirosa, K. Thompson, S. Bouralexis, E. C. Walker, T. J. Martin, and M. T. Gillespie IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice J. Immunol., October 15, 2008; 181(8): 5720 - 5729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lorenzo, M. Horowitz, and Y. Choi Osteoimmunology: Interactions of the Bone and Immune System Endocr. Rev., June 1, 2008; 29(4): 403 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stolina, D. Dwyer, M. S. Ominsky, T. Corbin, G. Van, B. Bolon, I. Sarosi, J. McCabe, D. J. Zack, and P. Kostenuik Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses J. Immunol., December 1, 2007; 179(11): 7497 - 7505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Taylor, S. R. Patel, E. Lin, B. R. Butler, J. G. Lake, R. D. Newberry, and I. R. Williams Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer's Patches J. Immunol., May 1, 2007; 178(9): 5659 - 5667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Maruyama, G.-i. Sano, N. Ray, Y. Takada, and K. Matsuo c-Fos-Deficient Mice Are Susceptible to Salmonella enterica Serovar Typhimurium Infection Infect. Immun., March 1, 2007; 75(3): 1520 - 1523. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
