IL-1 and TNF induction of matrix metalloproteinase-3 by c-Jun N-terminal kinase in trabecular meshwork

Mojgan Hosseini, Anastasia Y. Rose, Kaili Song, Cynthia Bohan, J. Preston Alexander, Mary Kelley, Ted Acott

Research output: Contribution to journalArticle

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Abstract

PURPOSE. The cytokines TNF and IL-1 mediate the MMP-3 increase that occurs in response to trabecular meshwork (TM) treatment by laser trabeculoplasty. This MMP-3 increase appears to play a key role in the efficacy of this treatment for open-angle glaucoma. Protein kinase Cμ and the Erk mitogen-activated protein (MAP) kinases are essential signaling components in transducing MMP-3 increases produced by treatment of TM cells with these cytokines. Here, the involvement of the JNK-MAP kinase pathway in this process was evaluated. METHODS. Porcine TM cells were treated with TNFα, IL-1α, or IL-1β. Changes in MMP-3 and MMP-9 protein levels in the media were then determined by Western immunoblot. The effect of JNK inhibitor 2 was evaluated. Changes in the level of phosphorylation of JNK, c-Jun, ATF-2, MKK4, and MKK7 were also determined at various times after TNFα or IL-1α treatment. A 2.3-kb MMP-3 promoter fragment was cloned into a secreted alkaline phosphatase reporter vector. This reporter construct was cotransfected into TM cells with a mammalian expression vector containing a dominant-negative mutant of JNK. The involvement of JNK activity in the TNFα and IL-1α induction of MMP-3 expression was then evaluated. RESULTS. TNFα, IL-1α, and IL-1β increase media MMP-3 and MMP-9 protein levels, and JNK inhibitor 2 blocks these increases. JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFα and IL-1α treatment. JNK inhibitor 2 pretreatment blocks these c-Jun and ATF-2 phosphorylation increases. Dominant-negative JNK dramatically reduces the MMP-3 promoter-driven reporter activity induced by these cytokines. CONCLUSIONS. JNK activity is necessary for the induction of MMP-3 and MMP-9 by TNFα, IL-1α, or IL-1β in TM cells. Phosphorylation of components of the JNK signaling pathway and of the transcription factors c-Jun and ATF-2 support a role for this pathway in the induction of MMP-3 and MMP-9 in the TM in response to these cytokines. Thus, at least three separate signal transduction pathways are necessary in this signaling event in TM cells.

Original languageEnglish (US)
Pages (from-to)1469-1476
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number4
DOIs
StatePublished - Apr 2006

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Trabecular Meshwork
Matrix Metalloproteinase 3
JNK Mitogen-Activated Protein Kinases
Matrix Metalloproteinases
Interleukin-1
Phosphorylation
Cytokines
Trabeculectomy
MAP Kinase Signaling System
Open Angle Glaucoma
Mitogen-Activated Protein Kinases
Protein Kinase C

ASJC Scopus subject areas

  • Ophthalmology

Cite this

IL-1 and TNF induction of matrix metalloproteinase-3 by c-Jun N-terminal kinase in trabecular meshwork. / Hosseini, Mojgan; Rose, Anastasia Y.; Song, Kaili; Bohan, Cynthia; Alexander, J. Preston; Kelley, Mary; Acott, Ted.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 4, 04.2006, p. 1469-1476.

Research output: Contribution to journalArticle

Hosseini, Mojgan ; Rose, Anastasia Y. ; Song, Kaili ; Bohan, Cynthia ; Alexander, J. Preston ; Kelley, Mary ; Acott, Ted. / IL-1 and TNF induction of matrix metalloproteinase-3 by c-Jun N-terminal kinase in trabecular meshwork. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 4. pp. 1469-1476.
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abstract = "PURPOSE. The cytokines TNF and IL-1 mediate the MMP-3 increase that occurs in response to trabecular meshwork (TM) treatment by laser trabeculoplasty. This MMP-3 increase appears to play a key role in the efficacy of this treatment for open-angle glaucoma. Protein kinase Cμ and the Erk mitogen-activated protein (MAP) kinases are essential signaling components in transducing MMP-3 increases produced by treatment of TM cells with these cytokines. Here, the involvement of the JNK-MAP kinase pathway in this process was evaluated. METHODS. Porcine TM cells were treated with TNFα, IL-1α, or IL-1β. Changes in MMP-3 and MMP-9 protein levels in the media were then determined by Western immunoblot. The effect of JNK inhibitor 2 was evaluated. Changes in the level of phosphorylation of JNK, c-Jun, ATF-2, MKK4, and MKK7 were also determined at various times after TNFα or IL-1α treatment. A 2.3-kb MMP-3 promoter fragment was cloned into a secreted alkaline phosphatase reporter vector. This reporter construct was cotransfected into TM cells with a mammalian expression vector containing a dominant-negative mutant of JNK. The involvement of JNK activity in the TNFα and IL-1α induction of MMP-3 expression was then evaluated. RESULTS. TNFα, IL-1α, and IL-1β increase media MMP-3 and MMP-9 protein levels, and JNK inhibitor 2 blocks these increases. JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFα and IL-1α treatment. JNK inhibitor 2 pretreatment blocks these c-Jun and ATF-2 phosphorylation increases. Dominant-negative JNK dramatically reduces the MMP-3 promoter-driven reporter activity induced by these cytokines. CONCLUSIONS. JNK activity is necessary for the induction of MMP-3 and MMP-9 by TNFα, IL-1α, or IL-1β in TM cells. Phosphorylation of components of the JNK signaling pathway and of the transcription factors c-Jun and ATF-2 support a role for this pathway in the induction of MMP-3 and MMP-9 in the TM in response to these cytokines. Thus, at least three separate signal transduction pathways are necessary in this signaling event in TM cells.",
author = "Mojgan Hosseini and Rose, {Anastasia Y.} and Kaili Song and Cynthia Bohan and Alexander, {J. Preston} and Mary Kelley and Ted Acott",
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T1 - IL-1 and TNF induction of matrix metalloproteinase-3 by c-Jun N-terminal kinase in trabecular meshwork

AU - Hosseini, Mojgan

AU - Rose, Anastasia Y.

AU - Song, Kaili

AU - Bohan, Cynthia

AU - Alexander, J. Preston

AU - Kelley, Mary

AU - Acott, Ted

PY - 2006/4

Y1 - 2006/4

N2 - PURPOSE. The cytokines TNF and IL-1 mediate the MMP-3 increase that occurs in response to trabecular meshwork (TM) treatment by laser trabeculoplasty. This MMP-3 increase appears to play a key role in the efficacy of this treatment for open-angle glaucoma. Protein kinase Cμ and the Erk mitogen-activated protein (MAP) kinases are essential signaling components in transducing MMP-3 increases produced by treatment of TM cells with these cytokines. Here, the involvement of the JNK-MAP kinase pathway in this process was evaluated. METHODS. Porcine TM cells were treated with TNFα, IL-1α, or IL-1β. Changes in MMP-3 and MMP-9 protein levels in the media were then determined by Western immunoblot. The effect of JNK inhibitor 2 was evaluated. Changes in the level of phosphorylation of JNK, c-Jun, ATF-2, MKK4, and MKK7 were also determined at various times after TNFα or IL-1α treatment. A 2.3-kb MMP-3 promoter fragment was cloned into a secreted alkaline phosphatase reporter vector. This reporter construct was cotransfected into TM cells with a mammalian expression vector containing a dominant-negative mutant of JNK. The involvement of JNK activity in the TNFα and IL-1α induction of MMP-3 expression was then evaluated. RESULTS. TNFα, IL-1α, and IL-1β increase media MMP-3 and MMP-9 protein levels, and JNK inhibitor 2 blocks these increases. JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFα and IL-1α treatment. JNK inhibitor 2 pretreatment blocks these c-Jun and ATF-2 phosphorylation increases. Dominant-negative JNK dramatically reduces the MMP-3 promoter-driven reporter activity induced by these cytokines. CONCLUSIONS. JNK activity is necessary for the induction of MMP-3 and MMP-9 by TNFα, IL-1α, or IL-1β in TM cells. Phosphorylation of components of the JNK signaling pathway and of the transcription factors c-Jun and ATF-2 support a role for this pathway in the induction of MMP-3 and MMP-9 in the TM in response to these cytokines. Thus, at least three separate signal transduction pathways are necessary in this signaling event in TM cells.

AB - PURPOSE. The cytokines TNF and IL-1 mediate the MMP-3 increase that occurs in response to trabecular meshwork (TM) treatment by laser trabeculoplasty. This MMP-3 increase appears to play a key role in the efficacy of this treatment for open-angle glaucoma. Protein kinase Cμ and the Erk mitogen-activated protein (MAP) kinases are essential signaling components in transducing MMP-3 increases produced by treatment of TM cells with these cytokines. Here, the involvement of the JNK-MAP kinase pathway in this process was evaluated. METHODS. Porcine TM cells were treated with TNFα, IL-1α, or IL-1β. Changes in MMP-3 and MMP-9 protein levels in the media were then determined by Western immunoblot. The effect of JNK inhibitor 2 was evaluated. Changes in the level of phosphorylation of JNK, c-Jun, ATF-2, MKK4, and MKK7 were also determined at various times after TNFα or IL-1α treatment. A 2.3-kb MMP-3 promoter fragment was cloned into a secreted alkaline phosphatase reporter vector. This reporter construct was cotransfected into TM cells with a mammalian expression vector containing a dominant-negative mutant of JNK. The involvement of JNK activity in the TNFα and IL-1α induction of MMP-3 expression was then evaluated. RESULTS. TNFα, IL-1α, and IL-1β increase media MMP-3 and MMP-9 protein levels, and JNK inhibitor 2 blocks these increases. JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFα and IL-1α treatment. JNK inhibitor 2 pretreatment blocks these c-Jun and ATF-2 phosphorylation increases. Dominant-negative JNK dramatically reduces the MMP-3 promoter-driven reporter activity induced by these cytokines. CONCLUSIONS. JNK activity is necessary for the induction of MMP-3 and MMP-9 by TNFα, IL-1α, or IL-1β in TM cells. Phosphorylation of components of the JNK signaling pathway and of the transcription factors c-Jun and ATF-2 support a role for this pathway in the induction of MMP-3 and MMP-9 in the TM in response to these cytokines. Thus, at least three separate signal transduction pathways are necessary in this signaling event in TM cells.

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