Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’

  • Authors:
    • Lijun Xin
    • Jing Wang
    • Hailong Zhang
    • Wenfang Shi
    • Mingxia Yu
    • Qingfen Li
    • Xiaodan Jiang
    • Feili Gong
    • Kevin Gardner
    • Qingdi Q. Li
    • Zhuoya Li
  • View Affiliations

  • Published online on: November 1, 2006     https://doi.org/10.3892/ijmm.18.5.885
  • Pages: 885-892
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Abstract

Transmembrane tumor necrosis factor-α (mTNF-α) is known to be the precursor of soluble TNF-α (sTNF-α). mTNF-α can act as a ligand on the TNF receptor- (TNFR)- bearing cell through ‘forward signaling’ or as a receptor on the TNF producing cell through ‘reverse signaling’. In the current study, we investigated the role of mTNF-α-mediated reverse signaling in regulating sTNF-α-induced activation of human monocytic U937 cells. We demonstrated that pretreatment with sTNFRI, for inducing reverse signaling through mTNF-α, sensitized U937 cells to sTNF-α stimulation, as evidenced by an increase in reactive oxygen production and mRNA levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-8) in these cells. Further experiments revealed that IκB-α degradation was increased in the monocytic cells primed with sTNFRI, implying that reverse signaling of mTNF-α sensitizes U937 cells via an NF-κB-dependent mechanism. On the other hand, binding of sTNFRI to mTNF-α after sTNF-α-induced activation of U937 cells reduced mRNA stability (half-life) of IL-1β and IL-8. The involvement of reverse signaling in the process was verified by using a mutated form of mTNF-α lacking the majority of the cytoplasmic domain. Our results clearly showed that enhanced mRNA degradation of the cytokines occurred only in U937 cells transfected with a wild-type mTNF-α, but not in those cells transfected with the mutant mTNF-α. Taken together, these data suggest that reverse signaling through mTNF-α may exert a double role in modulating sTNF-α bioactivity. It is positive when reverse signaling occurs prior to sTNF-α stimulation, while it is negative when reverse signaling occurs after the sTNF-α signal. Thus, our findings strengthen a role of mTNF-α-mediated reverse signaling in the regulation of immune-inflammatory response and control of inflammatory reaction.

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November 2006
Volume 18 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Xin L, Wang J, Zhang H, Shi W, Yu M, Li Q, Jiang X, Gong F, Gardner K, Li QQ, Li QQ, et al: Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’. Int J Mol Med 18: 885-892, 2006
APA
Xin, L., Wang, J., Zhang, H., Shi, W., Yu, M., Li, Q. ... Li, Z. (2006). Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’. International Journal of Molecular Medicine, 18, 885-892. https://doi.org/10.3892/ijmm.18.5.885
MLA
Xin, L., Wang, J., Zhang, H., Shi, W., Yu, M., Li, Q., Jiang, X., Gong, F., Gardner, K., Li, Q. Q., Li, Z."Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’". International Journal of Molecular Medicine 18.5 (2006): 885-892.
Chicago
Xin, L., Wang, J., Zhang, H., Shi, W., Yu, M., Li, Q., Jiang, X., Gong, F., Gardner, K., Li, Q. Q., Li, Z."Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’". International Journal of Molecular Medicine 18, no. 5 (2006): 885-892. https://doi.org/10.3892/ijmm.18.5.885