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Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB.
Am J Pathol. 2013 Jun; 182(6):2310-21.AJ

Abstract

We investigated TNF-α and IL-1β regulation of ADAMTS-4 expression in nucleus pulposus (NP) cells and its role in aggrecan degradation. Real-time quantitative RT-PCR, Western blotting, and transient transfections with rat NP cells and lentiviral silencing with human NP cells were performed to determine the roles of MAPK and NF-κB in cytokine-mediated ADAMTS-4 expression and function. ADAMTS4 expression and promoter activity increased in NP cells after TNF-α and IL-1β treatment. Treatment of cells with MAPK and NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS4 mRNA and protein expression. Although ERK1, p38α, p38β2, and p38γ were involved in induction, ERK2 and p38δ played no role in TNF-α-dependent promoter activity. The inductive effect of p65 on ADAMTS4 promoter was confirmed through gain and loss-of-function studies. Cotransfection of p50 completely blocked p65-mediated induction. Lentiviral transduction with shRNA plasmids shp65, shp52, shIKK-α, and shIKK-β significantly decreased TNF-α-dependent increase in ADAMTS-4 and -5 levels and aggrecan degradation. Silencing of either ADAMTS-4 or -5 resulted in reduction in TNF-α-dependent aggrecan degradation in NP cells. By controlling activation of MAPK and NF-κB signaling, TNF-α and IL-1β modulate expression of ADAMTS-4 in NP cells. To our knowledge, this is the first study to show nonredundant contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells in vitro.

Authors+Show Affiliations

Department of Orthopaedic Surgery and the 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 available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23602832

Citation

Tian, Ye, et al. "Inflammatory Cytokines Associated With Degenerative Disc Disease Control Aggrecanase-1 (ADAMTS-4) Expression in Nucleus Pulposus Cells Through MAPK and NF-κB." The American Journal of Pathology, vol. 182, no. 6, 2013, pp. 2310-21.
Tian Y, Yuan W, Fujita N, et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310-21.
Tian, Y., Yuan, W., Fujita, N., Wang, J., Wang, H., Shapiro, I. M., & Risbud, M. V. (2013). Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. The American Journal of Pathology, 182(6), 2310-21. https://doi.org/10.1016/j.ajpath.2013.02.037
Tian Y, et al. Inflammatory Cytokines Associated With Degenerative Disc Disease Control Aggrecanase-1 (ADAMTS-4) Expression in Nucleus Pulposus Cells Through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310-21. PubMed PMID: 23602832.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. AU - Tian,Ye, AU - Yuan,Wen, AU - Fujita,Nobuyuki, AU - Wang,Jianru, AU - Wang,Hua, AU - Shapiro,Irving M, AU - Risbud,Makarand V, Y1 - 2013/04/17/ PY - 2012/11/16/received PY - 2013/01/18/revised PY - 2013/02/19/accepted PY - 2013/4/23/entrez PY - 2013/4/23/pubmed PY - 2013/11/6/medline SP - 2310 EP - 21 JF - The American journal of pathology JO - Am. J. Pathol. VL - 182 IS - 6 N2 - We investigated TNF-α and IL-1β regulation of ADAMTS-4 expression in nucleus pulposus (NP) cells and its role in aggrecan degradation. Real-time quantitative RT-PCR, Western blotting, and transient transfections with rat NP cells and lentiviral silencing with human NP cells were performed to determine the roles of MAPK and NF-κB in cytokine-mediated ADAMTS-4 expression and function. ADAMTS4 expression and promoter activity increased in NP cells after TNF-α and IL-1β treatment. Treatment of cells with MAPK and NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS4 mRNA and protein expression. Although ERK1, p38α, p38β2, and p38γ were involved in induction, ERK2 and p38δ played no role in TNF-α-dependent promoter activity. The inductive effect of p65 on ADAMTS4 promoter was confirmed through gain and loss-of-function studies. Cotransfection of p50 completely blocked p65-mediated induction. Lentiviral transduction with shRNA plasmids shp65, shp52, shIKK-α, and shIKK-β significantly decreased TNF-α-dependent increase in ADAMTS-4 and -5 levels and aggrecan degradation. Silencing of either ADAMTS-4 or -5 resulted in reduction in TNF-α-dependent aggrecan degradation in NP cells. By controlling activation of MAPK and NF-κB signaling, TNF-α and IL-1β modulate expression of ADAMTS-4 in NP cells. To our knowledge, this is the first study to show nonredundant contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells in vitro. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/23602832/Inflammatory_cytokines_associated_with_degenerative_disc_disease_control_aggrecanase_1__ADAMTS_4__expression_in_nucleus_pulposus_cells_through_MAPK_and_NF_κB_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(13)00216-2 DB - PRIME DP - Unbound Medicine ER -