Synergism of TNF and IL-1 in the induction of matrix metalloproteinase-3 in trabecular meshwork

Mary Kelley, Anastasia Y. Rose, Kaili Song, Yanwen Chen, John M. Bradley, Derek Rookhuizen, Ted Acott

Research output: Contribution to journalArticle

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Abstract

PURPOSE. TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in the trabecular meshwork (TM). TNF-α, in combination with IL-1α or IL-1β, produces highly synergistic MMP-3 increases. Possible mechanisms for this synergism in TM cells were investigated. METHODS. Porcine and human TM cells were treated with TNF-α, IL-1α, IL-1β and their combinations. Western immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-α, IL-1α, IL-1β, IL-6, TNF receptor I (RI), IL-1 RI, and IL-1 RII levels and the phosphorylation of Erk, JNK, and p38 MAP kinases. Dose-response effects for TNF-α, IL-1α and IL-1β on MMP-3 were evaluated. Microarray and quantitative RT-PCR were used to determine mRNA levels. MMP-3 transcription rate was assessed by transfecting TM cells with an MMP-3 promoter/reporter construct. Combined cytokine effects on outflow facility were appraised in perfused anterior segment organ culture. RESULTS. TNF-α, IL-1α, and IL-1β each individually increased MMP-3 levels, whereas TNF-α in combination with IL-1α or IL-1β produced highly synergistic increases. MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed synergism. IL-1α, IL-1β, and IL-6, but not TNF-α mRNA or protein level, were elevated by these cytokines. Maximum MMP-3 production for individual cytokines, even at high doses, was far less than with dual cytokine doses. Erk 1 and 2, JNK 1 and 2, and p38 α and β phosphorylation increased, but not synergistically. However, phosphorylation of novel isoforms of JNK and p38 δ and γ did show synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. TNF-α significantly increased IL-1 RI levels. Synergism in outflow facility was observed with TNF-α and IL-1α. CONCLUSIONS. TNF-α, in combination with IL-1α or IL-1β, produced intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF-α partially explains the synergism. Responses of novel JNK and p38 MAP kinase δ and γ isoforms also partially account for the synergism. Understanding this strong synergistic effect may provide useful insight into optimizing therapeutic regulation of intraocular pressure in glaucoma.

Original languageEnglish (US)
Pages (from-to)2634-2643
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number6
DOIs
StatePublished - Jun 2007

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Trabecular Meshwork
Matrix Metalloproteinase 3
Interleukin-1
Matrix Metalloproteinases
Interleukin-1 Receptors
Cytokines
Phosphorylation
p38 Mitogen-Activated Protein Kinases
Messenger RNA
Protein Isoforms
Interleukin-6 Receptors

ASJC Scopus subject areas

  • Ophthalmology

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Synergism of TNF and IL-1 in the induction of matrix metalloproteinase-3 in trabecular meshwork. / Kelley, Mary; Rose, Anastasia Y.; Song, Kaili; Chen, Yanwen; Bradley, John M.; Rookhuizen, Derek; Acott, Ted.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 6, 06.2007, p. 2634-2643.

Research output: Contribution to journalArticle

Kelley, Mary ; Rose, Anastasia Y. ; Song, Kaili ; Chen, Yanwen ; Bradley, John M. ; Rookhuizen, Derek ; Acott, Ted. / Synergism of TNF and IL-1 in the induction of matrix metalloproteinase-3 in trabecular meshwork. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 6. pp. 2634-2643.
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abstract = "PURPOSE. TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in the trabecular meshwork (TM). TNF-α, in combination with IL-1α or IL-1β, produces highly synergistic MMP-3 increases. Possible mechanisms for this synergism in TM cells were investigated. METHODS. Porcine and human TM cells were treated with TNF-α, IL-1α, IL-1β and their combinations. Western immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-α, IL-1α, IL-1β, IL-6, TNF receptor I (RI), IL-1 RI, and IL-1 RII levels and the phosphorylation of Erk, JNK, and p38 MAP kinases. Dose-response effects for TNF-α, IL-1α and IL-1β on MMP-3 were evaluated. Microarray and quantitative RT-PCR were used to determine mRNA levels. MMP-3 transcription rate was assessed by transfecting TM cells with an MMP-3 promoter/reporter construct. Combined cytokine effects on outflow facility were appraised in perfused anterior segment organ culture. RESULTS. TNF-α, IL-1α, and IL-1β each individually increased MMP-3 levels, whereas TNF-α in combination with IL-1α or IL-1β produced highly synergistic increases. MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed synergism. IL-1α, IL-1β, and IL-6, but not TNF-α mRNA or protein level, were elevated by these cytokines. Maximum MMP-3 production for individual cytokines, even at high doses, was far less than with dual cytokine doses. Erk 1 and 2, JNK 1 and 2, and p38 α and β phosphorylation increased, but not synergistically. However, phosphorylation of novel isoforms of JNK and p38 δ and γ did show synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. TNF-α significantly increased IL-1 RI levels. Synergism in outflow facility was observed with TNF-α and IL-1α. CONCLUSIONS. TNF-α, in combination with IL-1α or IL-1β, produced intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF-α partially explains the synergism. Responses of novel JNK and p38 MAP kinase δ and γ isoforms also partially account for the synergism. Understanding this strong synergistic effect may provide useful insight into optimizing therapeutic regulation of intraocular pressure in glaucoma.",
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T1 - Synergism of TNF and IL-1 in the induction of matrix metalloproteinase-3 in trabecular meshwork

AU - Kelley, Mary

AU - Rose, Anastasia Y.

AU - Song, Kaili

AU - Chen, Yanwen

AU - Bradley, John M.

AU - Rookhuizen, Derek

AU - Acott, Ted

PY - 2007/6

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N2 - PURPOSE. TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in the trabecular meshwork (TM). TNF-α, in combination with IL-1α or IL-1β, produces highly synergistic MMP-3 increases. Possible mechanisms for this synergism in TM cells were investigated. METHODS. Porcine and human TM cells were treated with TNF-α, IL-1α, IL-1β and their combinations. Western immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-α, IL-1α, IL-1β, IL-6, TNF receptor I (RI), IL-1 RI, and IL-1 RII levels and the phosphorylation of Erk, JNK, and p38 MAP kinases. Dose-response effects for TNF-α, IL-1α and IL-1β on MMP-3 were evaluated. Microarray and quantitative RT-PCR were used to determine mRNA levels. MMP-3 transcription rate was assessed by transfecting TM cells with an MMP-3 promoter/reporter construct. Combined cytokine effects on outflow facility were appraised in perfused anterior segment organ culture. RESULTS. TNF-α, IL-1α, and IL-1β each individually increased MMP-3 levels, whereas TNF-α in combination with IL-1α or IL-1β produced highly synergistic increases. MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed synergism. IL-1α, IL-1β, and IL-6, but not TNF-α mRNA or protein level, were elevated by these cytokines. Maximum MMP-3 production for individual cytokines, even at high doses, was far less than with dual cytokine doses. Erk 1 and 2, JNK 1 and 2, and p38 α and β phosphorylation increased, but not synergistically. However, phosphorylation of novel isoforms of JNK and p38 δ and γ did show synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. TNF-α significantly increased IL-1 RI levels. Synergism in outflow facility was observed with TNF-α and IL-1α. CONCLUSIONS. TNF-α, in combination with IL-1α or IL-1β, produced intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF-α partially explains the synergism. Responses of novel JNK and p38 MAP kinase δ and γ isoforms also partially account for the synergism. Understanding this strong synergistic effect may provide useful insight into optimizing therapeutic regulation of intraocular pressure in glaucoma.

AB - PURPOSE. TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in the trabecular meshwork (TM). TNF-α, in combination with IL-1α or IL-1β, produces highly synergistic MMP-3 increases. Possible mechanisms for this synergism in TM cells were investigated. METHODS. Porcine and human TM cells were treated with TNF-α, IL-1α, IL-1β and their combinations. Western immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-α, IL-1α, IL-1β, IL-6, TNF receptor I (RI), IL-1 RI, and IL-1 RII levels and the phosphorylation of Erk, JNK, and p38 MAP kinases. Dose-response effects for TNF-α, IL-1α and IL-1β on MMP-3 were evaluated. Microarray and quantitative RT-PCR were used to determine mRNA levels. MMP-3 transcription rate was assessed by transfecting TM cells with an MMP-3 promoter/reporter construct. Combined cytokine effects on outflow facility were appraised in perfused anterior segment organ culture. RESULTS. TNF-α, IL-1α, and IL-1β each individually increased MMP-3 levels, whereas TNF-α in combination with IL-1α or IL-1β produced highly synergistic increases. MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed synergism. IL-1α, IL-1β, and IL-6, but not TNF-α mRNA or protein level, were elevated by these cytokines. Maximum MMP-3 production for individual cytokines, even at high doses, was far less than with dual cytokine doses. Erk 1 and 2, JNK 1 and 2, and p38 α and β phosphorylation increased, but not synergistically. However, phosphorylation of novel isoforms of JNK and p38 δ and γ did show synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. TNF-α significantly increased IL-1 RI levels. Synergism in outflow facility was observed with TNF-α and IL-1α. CONCLUSIONS. TNF-α, in combination with IL-1α or IL-1β, produced intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF-α partially explains the synergism. Responses of novel JNK and p38 MAP kinase δ and γ isoforms also partially account for the synergism. Understanding this strong synergistic effect may provide useful insight into optimizing therapeutic regulation of intraocular pressure in glaucoma.

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