PMID- 17525194
OWN - NLM
STAT- MEDLINE
DCOM- 20070702
LR  - 20220310
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 48
IP  - 6
DP  - 2007 Jun
TI  - Synergism of TNF and IL-1 in the induction of matrix metalloproteinase-3 in 
      trabecular meshwork.
PG  - 2634-43
AB  - PURPOSE: TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in 
      the trabecular meshwork (TM). TNF-alpha, in combination with IL-1alpha or 
      IL-1beta, 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-alpha, IL-1alpha, IL-1beta and their combinations. Western 
      immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-alpha, IL-1alpha, 
      IL-1beta, 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-alpha, IL-1alpha and IL-1beta 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-alpha, IL-1alpha, and IL-1beta each 
      individually increased MMP-3 levels, whereas TNF-alpha in combination with 
      IL-1alpha or IL-1beta produced highly synergistic increases. MMP-9 and MMP-12 
      levels were also elevated, but only MMP-12 showed synergism. IL-1alpha, IL-1beta, 
      and IL-6, but not TNF-alpha 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 
      alpha and beta phosphorylation increased, but not synergistically. However, 
      phosphorylation of novel isoforms of JNK and p38 delta and gamma did show 
      synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. 
      TNF-alpha significantly increased IL-1 RI levels. Synergism in outflow facility 
      was observed with TNF-alpha and IL-1alpha. CONCLUSIONS: TNF-alpha, in combination 
      with IL-1alpha or IL-1beta, produced intense synergistic increases in MMP-3 and 
      MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF-alpha partially explains the 
      synergism. Responses of novel JNK and p38 MAP kinase delta and gamma 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.
FAU - Kelley, Mary J
AU  - Kelley MJ
AD  - Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 
      97239-4197, USA.
FAU - Rose, Anastasia Y
AU  - Rose AY
FAU - Song, Kaili
AU  - Song K
FAU - Chen, Yanwen
AU  - Chen Y
FAU - Bradley, John M
AU  - Bradley JM
FAU - Rookhuizen, Derek
AU  - Rookhuizen D
FAU - Acott, Ted S
AU  - Acott TS
LA  - eng
GR  - EY003279/EY/NEI NIH HHS/United States
GR  - EY008247/EY/NEI NIH HHS/United States
GR  - EY010572/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Interleukin 1 Receptor Antagonist Protein)
RN  - 0 (Interleukin-1alpha)
RN  - 0 (Interleukin-1beta)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.65 (Matrix Metalloproteinase 12)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Culture Techniques
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Humans
MH  - Interleukin 1 Receptor Antagonist Protein/metabolism
MH  - Interleukin-1alpha/*pharmacology
MH  - Interleukin-1beta/*pharmacology
MH  - MAP Kinase Kinase 4/metabolism
MH  - Matrix Metalloproteinase 12/biosynthesis
MH  - Matrix Metalloproteinase 3/*biosynthesis/genetics
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phosphorylation
MH  - RNA, Messenger/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Swine
MH  - Trabecular Meshwork/*drug effects/enzymology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2007/05/26 09:00
MHDA- 2007/07/03 09:00
CRDT- 2007/05/26 09:00
PHST- 2007/05/26 09:00 [pubmed]
PHST- 2007/07/03 09:00 [medline]
PHST- 2007/05/26 09:00 [entrez]
AID - 48/6/2634 [pii]
AID - 10.1167/iovs.06-1445 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2634-43. doi: 10.1167/iovs.06-1445.