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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #253878
Title: Suppressor of cytokine signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing CCAAT/enhancer-binding protein ß activity

Author
item YAN, CHUNGUANG - Harvard Medical School
item Cao, Jay
item WU, MIN - University Of North Dakota
item JIANG, TAO - Harvard Medical School
item YOSHIMURA, AKIHIKO - Keio University
item GAO, HONGWEI - Harvard Medical School
item ZHANG, WEI - Harvard Medical School

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/25/2010
Publication Date: 11/26/2010
Citation: Yan, C., Cao, J.J., Wu, M., Jiang, T., Yoshimura, A., Gao, H., Zhang, W. 2010. Suppressor of cytokine signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing CCAAT/enhancer-binding protein ß activity. Journal of Biological Chemistry. 285(48):37227-37239.

Interpretive Summary: Bacteria-induced activation of inflammatory changes causes bone loss. LPS is a component found in the outer cell membrane of gram-negative bacteria that increases bone resorption. LPS stimulates osteoclastogenesis through upregulation of RANKL, IL-6, IL-1, and TNF-a. Suppressors of cytokine signaling 3 (SOCS3) is an important intracellular regulator of TLR4 signaling and plays an important role in several inflammatory diseases. We demonstrated that LPS transiently induced SOCS3 expression in osteoblasts, and SOCS3 apparently contributes to the inhibition of LPS- induced IL-6 expression. We also found that both the N-terminal kinase inhibitory region and the SH2 domain of SOCS3 are involved in its IL-6 inhibition while kinase inhibitory region was indispensible for this effect. Furthermore, we demonstrated that LPS activates CCAAT/enhancerbinding protein (C/EBP) ß and C/EBP plays a key role in LPS-induced IL-6 expression in osteoblasts. We further provide the evidence that SOCS3 functions as a negative regulator for TLR4 response in osteoblasts by suppressing C/EBPß activity. In addition, we show that the N-terminal kinase inhibitory region of SOCS3 is required for its C/EBP inhibition. Our data indicate that SOCS3 may be an important regulator in bone-associated inflammatory responses by interfering with C/EBPß activation.

Technical Abstract: Suppressors of cytokine signaling 3 (SOCS3) is an important intracellular regulator of TLR4 signaling and has been implicated in several inflammatory diseases. Although SOCS3 seems to contribute to the balance between the pro-inflammatory effects of IL-6 and antiinflammatory signaling of IL-10 by negatively regulating IL-6/gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream effects of TLR4 are largely unknown and still controversial. Furthermore, very little is known regarding its expression and function in osteoblasts. In this study, we demonstrated that SOCS3 expression was transiently induced by LPS in osteoblasts, and apparently contributes to the inhibition of IL-6 induction by LPS treatment. We found that both the N-terminal kinase inhibitory region (KIR) and the SH2 domain of SOCS3 are involved in its IL-6 inhibition whileKIR was necessary for this effect. Furthermore, we demonstrated that CCAAT/enhancerbindin protein (C/EBP) ß is activated by LPS, and plays a key role in LPS-induced IL-6 expression in osteoblasts. We further provide the evidence that SOCS3 functions as a negative regulator for TLR4 response in osteoblasts by suppressing C/EBPß activity. In addition, we show that the KIR of SOCS3 is required for its C/EBP inhibition. These findings suggest that SOCS3 by interfering with C/EBPß activation may have an important regulatory role during bone-associated inflammatory responses.