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Inflammatory cytokines induce NOTCH signaling in nucleus pulposus cells: implications in intervertebral disc degeneration.
J Biol Chem. 2013 Jun 07; 288(23):16761-74.JB

Abstract

The objective of the study was to investigate how inflammatory cytokines, IL-1β, and TNF-α control NOTCH signaling activity in nucleus pulposus (NP) cells. An increase in expression of selective NOTCH receptors (NOTCH1 and -2), ligand (JAGGED2), and target genes (HES1, HEY1, and HEY2) was observed in NP cells following cytokine treatment. A concomitant increase in NOTCH signaling as evidenced by induction in activity of target gene HES1 and HEY1 promoters and reporter 12xCSL was seen. Moreover, treatment increased activity of a 2-kb NOTCH2 promoter. Treatment of cells with NF-κB and MAPK inhibitors abolished the inductive effect of cytokines on NOTCH2 promoter and its expression. Gain and loss-of-function studies confirmed the inductive effect of p65 on NOTCH2 promoter activity. In contrast, p50 blocked the cytokine induction of promoter activity. Supporting promoter studies, lentiviral delivery of sh-p65, and sh-IKKβ significantly decreased cytokine dependent change in NOTCH2 expression. Interestingly, MAPK signaling showed an isoform-specific control of NOTCH2 promoter; p38α/β2/δ, ERK1, and ERK2 contributed to cytokine dependent induction, whereas p38γ played no role. Analysis of human NP tissues showed that NOTCH1 and -2 and HEY2 expression correlated with each other. Moreover, expression of NOTCH2 and IL-1β as well as the number of cells immunopositive for NOTCH2 significantly increased in histologically degenerate discs compared with non-degenerate discs. Taken together, these results explain the observed dysregulated expression of NOTCH genes in degenerative disc disease. Thus, controlling IL-1β and TNF-α activities during disc disease may restore NOTCH signaling and nucleus pulposus cell function.

Authors+Show Affiliations

Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23589286

Citation

Wang, Hua, et al. "Inflammatory Cytokines Induce NOTCH Signaling in Nucleus Pulposus Cells: Implications in Intervertebral Disc Degeneration." The Journal of Biological Chemistry, vol. 288, no. 23, 2013, pp. 16761-74.
Wang H, Tian Y, Wang J, et al. Inflammatory cytokines induce NOTCH signaling in nucleus pulposus cells: implications in intervertebral disc degeneration. J Biol Chem. 2013;288(23):16761-74.
Wang, H., Tian, Y., Wang, J., Phillips, K. L., Binch, A. L., Dunn, S., Cross, A., Chiverton, N., Zheng, Z., Shapiro, I. M., Le Maitre, C. L., & Risbud, M. V. (2013). Inflammatory cytokines induce NOTCH signaling in nucleus pulposus cells: implications in intervertebral disc degeneration. The Journal of Biological Chemistry, 288(23), 16761-74. https://doi.org/10.1074/jbc.M112.446633
Wang H, et al. Inflammatory Cytokines Induce NOTCH Signaling in Nucleus Pulposus Cells: Implications in Intervertebral Disc Degeneration. J Biol Chem. 2013 Jun 7;288(23):16761-74. PubMed PMID: 23589286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inflammatory cytokines induce NOTCH signaling in nucleus pulposus cells: implications in intervertebral disc degeneration. AU - Wang,Hua, AU - Tian,Ye, AU - Wang,Jianru, AU - Phillips,Kate L E, AU - Binch,Abbie L A, AU - Dunn,Sara, AU - Cross,Alison, AU - Chiverton,Neil, AU - Zheng,Zhaomin, AU - Shapiro,Irving M, AU - Le Maitre,Christine L, AU - Risbud,Makarand V, Y1 - 2013/04/15/ PY - 2013/4/17/entrez PY - 2013/4/17/pubmed PY - 2013/8/13/medline KW - Chondrocytes KW - Cytokine KW - Intervertebral Disc KW - NF-kappa B (NF-KB) KW - Notch Pathway KW - Nucleus Pulposus KW - Osteoarthritis SP - 16761 EP - 74 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 23 N2 - The objective of the study was to investigate how inflammatory cytokines, IL-1β, and TNF-α control NOTCH signaling activity in nucleus pulposus (NP) cells. An increase in expression of selective NOTCH receptors (NOTCH1 and -2), ligand (JAGGED2), and target genes (HES1, HEY1, and HEY2) was observed in NP cells following cytokine treatment. A concomitant increase in NOTCH signaling as evidenced by induction in activity of target gene HES1 and HEY1 promoters and reporter 12xCSL was seen. Moreover, treatment increased activity of a 2-kb NOTCH2 promoter. Treatment of cells with NF-κB and MAPK inhibitors abolished the inductive effect of cytokines on NOTCH2 promoter and its expression. Gain and loss-of-function studies confirmed the inductive effect of p65 on NOTCH2 promoter activity. In contrast, p50 blocked the cytokine induction of promoter activity. Supporting promoter studies, lentiviral delivery of sh-p65, and sh-IKKβ significantly decreased cytokine dependent change in NOTCH2 expression. Interestingly, MAPK signaling showed an isoform-specific control of NOTCH2 promoter; p38α/β2/δ, ERK1, and ERK2 contributed to cytokine dependent induction, whereas p38γ played no role. Analysis of human NP tissues showed that NOTCH1 and -2 and HEY2 expression correlated with each other. Moreover, expression of NOTCH2 and IL-1β as well as the number of cells immunopositive for NOTCH2 significantly increased in histologically degenerate discs compared with non-degenerate discs. Taken together, these results explain the observed dysregulated expression of NOTCH genes in degenerative disc disease. Thus, controlling IL-1β and TNF-α activities during disc disease may restore NOTCH signaling and nucleus pulposus cell function. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23589286/Inflammatory_cytokines_induce_NOTCH_signaling_in_nucleus_pulposus_cells:_implications_in_intervertebral_disc_degeneration_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23589286 DB - PRIME DP - Unbound Medicine ER -