IL-10 Suppresses Calcium-Mediated Costimulation of Receptor Activator NF-kappa B Signaling during Human Osteoclast Differentiation by Inhibiting TREM-2 Expression
- Authors
- Park-Min, Kyung-Hyun; Ji, Jong-Dae; Antoniv, Taras; Reid, Alicia C.; Silver, Randi B.; Humphrey, Mary Beth; Nakamura, Mary; Ivashkiv, Lionel B.
- Issue Date
- 15-8월-2009
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- ALVEOLAR BONE LOSS; CUTTING EDGE; ADAPTER PROTEINS; GENE-EXPRESSION; IN-VIVO; C-FOS; INTERLEUKIN-10; RANKL; TRANSCRIPTION; CELLS
- Citation
- JOURNAL OF IMMUNOLOGY, v.183, no.4, pp.2444 - 2455
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 183
- Number
- 4
- Start Page
- 2444
- End Page
- 2455
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/119486
- DOI
- 10.4049/jimmunol.0804165
- ISSN
- 0022-1767
- Abstract
- Induction of effective osteoclastogenesis by RANK (receptor activator of NF-kappa B) requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 (triggering receptor expressed on myeloid cells 2) ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of calcium/calmodulin-dependent protein kinase (CaMK)II and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Down-regulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and they identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members. The Journal of Immunology, 2009, 183: 2444-2455.
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