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Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways.
J Immunol. 2000 Nov 15; 165(10):5788-97.JI

Abstract

The modulation of cell signaling by free radicals is important for the pathogenesis of inflammatory diseases. Recently, we have shown that NO reduces IL-1beta-induced matrix metalloproteinase (MMP-9) expression in glomerular mesangial cells (MC). Here we report that exogenously administrated superoxide, generated by the hypoxanthine/xanthine oxidase system (HXXO) or by the redox cycler 2, 3-dimethoxy-1,4-naphtoquinone, caused a marked amplification of IL-1beta-primed, steady state, MMP-9 mRNA level and an increase in gelatinolytic activity in the conditioned medium. Superoxide generators alone were ineffective. Cytokine-induced steady state mRNA levels of TIMP-1, an endogenous inhibitor of MMP-9, were affected similarly by HXXO. Transient transfection of rat mesangial cells with 0.6 kb of the 5'-flanking region of the rat MMP-9 gene proved a transcriptional regulation of MMP-9 expression by superoxide. HXXO augmented the IL-1beta-triggered nuclear translocation of p65 and c-Jun and, in parallel, increased DNA binding activities of NF-kappaB and AP-1. Mutation of either response element completely prevented MMP-9 promoter activation by IL-1beta. Moreover, specific inhibitors of the classical extracellular signal-regulated kinase (ERK) pathway and p38 mitogen-activated protein kinase (MAPK) cascade, partially reversed the HXXO-mediated effects on MMP-9 mRNA levels, thus demonstrating involvement of ERKs and p38 MAPKs in MMP-9 expression. Furthermore, IL-1beta-triggered phosphorylation of all three MAPKs, including p38-MAPK, c-Jun N-terminal kinase, and ERK, was substantially enhanced by superoxide. Our data identify superoxide as a costimulatory factor amplifying cytokine-induced MMP-9 expression by interfering with the signaling cascades leading to the activation of AP-1 and NF-kappaB.

Authors+Show Affiliations

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11067938

Citation

Eberhardt, W, et al. "Amplification of IL-1 Beta-induced Matrix Metalloproteinase-9 Expression By Superoxide in Rat Glomerular Mesangial Cells Is Mediated By Increased Activities of NF-kappa B and Activating Protein-1 and Involves Activation of the Mitogen-activated Protein Kinase Pathways." Journal of Immunology (Baltimore, Md. : 1950), vol. 165, no. 10, 2000, pp. 5788-97.
Eberhardt W, Huwiler A, Beck KF, et al. Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J Immunol. 2000;165(10):5788-97.
Eberhardt, W., Huwiler, A., Beck, K. F., Walpen, S., & Pfeilschifter, J. (2000). Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. Journal of Immunology (Baltimore, Md. : 1950), 165(10), 5788-97.
Eberhardt W, et al. Amplification of IL-1 Beta-induced Matrix Metalloproteinase-9 Expression By Superoxide in Rat Glomerular Mesangial Cells Is Mediated By Increased Activities of NF-kappa B and Activating Protein-1 and Involves Activation of the Mitogen-activated Protein Kinase Pathways. J Immunol. 2000 Nov 15;165(10):5788-97. PubMed PMID: 11067938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. AU - Eberhardt,W, AU - Huwiler,A, AU - Beck,K F, AU - Walpen,S, AU - Pfeilschifter,J, PY - 2000/11/9/pubmed PY - 2001/2/28/medline PY - 2000/11/9/entrez SP - 5788 EP - 97 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 165 IS - 10 N2 - The modulation of cell signaling by free radicals is important for the pathogenesis of inflammatory diseases. Recently, we have shown that NO reduces IL-1beta-induced matrix metalloproteinase (MMP-9) expression in glomerular mesangial cells (MC). Here we report that exogenously administrated superoxide, generated by the hypoxanthine/xanthine oxidase system (HXXO) or by the redox cycler 2, 3-dimethoxy-1,4-naphtoquinone, caused a marked amplification of IL-1beta-primed, steady state, MMP-9 mRNA level and an increase in gelatinolytic activity in the conditioned medium. Superoxide generators alone were ineffective. Cytokine-induced steady state mRNA levels of TIMP-1, an endogenous inhibitor of MMP-9, were affected similarly by HXXO. Transient transfection of rat mesangial cells with 0.6 kb of the 5'-flanking region of the rat MMP-9 gene proved a transcriptional regulation of MMP-9 expression by superoxide. HXXO augmented the IL-1beta-triggered nuclear translocation of p65 and c-Jun and, in parallel, increased DNA binding activities of NF-kappaB and AP-1. Mutation of either response element completely prevented MMP-9 promoter activation by IL-1beta. Moreover, specific inhibitors of the classical extracellular signal-regulated kinase (ERK) pathway and p38 mitogen-activated protein kinase (MAPK) cascade, partially reversed the HXXO-mediated effects on MMP-9 mRNA levels, thus demonstrating involvement of ERKs and p38 MAPKs in MMP-9 expression. Furthermore, IL-1beta-triggered phosphorylation of all three MAPKs, including p38-MAPK, c-Jun N-terminal kinase, and ERK, was substantially enhanced by superoxide. Our data identify superoxide as a costimulatory factor amplifying cytokine-induced MMP-9 expression by interfering with the signaling cascades leading to the activation of AP-1 and NF-kappaB. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/11067938/Amplification_of_IL_1_beta_induced_matrix_metalloproteinase_9_expression_by_superoxide_in_rat_glomerular_mesangial_cells_is_mediated_by_increased_activities_of_NF_kappa_B_and_activating_protein_1_and_involves_activation_of_the_mitogen_activated_protein_kinase_pathways_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11067938 DB - PRIME DP - Unbound Medicine ER -