Cytokines and signaling pathways regulating matrix metalloproteinase-9 (MMP-9) expression in corneal epithelial cells.

Full Abstract

Matrix metalloproteinase-9 (MMP-9) is a well-known regulator and effecter of many cellular processes including wound healing. In the cornea, either too much or too little MMP-9 can be detrimental to overall wound repair. We investigated the secreted factors as well as the intracellular signaling pathways and the promoter sequences that mediate this regulation. Primary culture rabbit corneal epithelial cells were treated with various cytokines alone or in different combinations and MMP-9 induction was assessed by gel zymography. Pharmacological inhibitors were used to determine the intracellular signaling pathways induced by the cytokines tested and deletion promoter constructs were created to determine the regions of the MMP-9 promoter involved in the cytokine regulation, thereby assessing the exact transcription factors binding the MMP-9 promoter. We found that two cytokine families, transforming growth factor beta (TGF-beta) and interleukin 1 (IL-1), act additively in an isoform non-specific manner to induce MMP-9 in this cell type. Our data suggest TGF-beta mediated MMP-9 induction may be regulated by the NF-kappaB, Smad3, and JNK pathways, whereas the IL-1beta mediated induction may be regulated by the NF-kappaB and p38 pathways. Inhibition of the p38, NF-kappaB, or JNK pathways significantly reduced, but did not abrogate, basal MMP-9 levels. Inhibition of the ERK pathway did not have an effect on MMP-9 mediated expression in either the treated or untreated co-transfected cells.

Author information

Author/s: Gordon, Gabriel M (GM); Ledee, Dolena R (DR); Feuer, William J (WJ); Fini, M Elizabeth (ME);

Affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.

Grants: P30 EY14801 (Agency:NEI NIH HHS) ; R01 EY09828 (Agency:NEI NIH HHS) ; R01 EY12651 (Agency:NEI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of cellular physiology (J Cell Physiol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 221 (issue 2) : pp 402-11

Dates: Created 2009/08/27; Completed 2009/09/09;

PMID: 19626678, status: MEDLINE (last retrieval date: 9/9/2009, IMS Date: )

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