PMID- 9840619
OWN - NLM
STAT- MEDLINE
DCOM- 19981223
LR  - 20071114
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 78
IP  - 11
DP  - 1998 Nov
TI  - The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the 
      pathogenesis of experimental autoimmune encephalomyelitis.
PG  - 1445-58
AB  - Previous studies have suggested that surface expression of alpha4 integrin by 
      autoreactive T-cell clones is necessary for the clones to induce experimental 
      autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. 
      To provide direct evidence for this phenomenon, we have transfected alpha4 
      integrin into C19alpha4-LO, a myelin basic protein-reactive T-cell clone that 
      does not express alpha4 integrin and does not induce EAE when adoptively 
      transferred into a susceptible mouse strain. Transfection of alpha4 integrin 
      converted this clone to an alpha4 integrin-expressing clone that induced EAE. We 
      then examined potential mechanisms by which alpha4 integrin may facilitate the 
      disease process. C19 T-cell clones adhered equally to a monolayer of 
      microvascular endothelial cells, regardless of level of alpha4 integrin 
      expression. However, in contrast to T-cell clones that do not express alpha4 
      integrin, T-cell clones that express alpha4 integrin (endogenously or by 
      transfection) transmigrated through an endothelial cell layer and subendothelial 
      matrix at an enhanced rate and adhered to recombinant vascular cell adhesion 
      molecule-1 (rVCAM-1) and the CS1 fragment of fibronectin, and after adhesion to 
      these ligands, a matrix-degrading metalloproteinase (MMP-2) was induced and 
      activated. The clones were also shown to constitutively express the membrane-type 
      matrix metalloproteinase (MT1-MMP), an enzyme that activates MMP-2. GM6001 and 
      UK-221,316, inhibitors of metalloproteinases, reduced alpha4 integrin-mediated 
      transmigration and EAE induction by C19 T-cell clones. In addition, we studied a 
      second EAE-inducing T-cell clone, MM4, which constitutively expresses alpha4 
      integrin and MMP-2. Engagement of alpha4 integrin on the MM4 clone up-regulated 
      the expression and activation of MMP-2, without changing the expression of 
      MT1-MMP. MMP inhibitors also reduced transmigration of and EAE induction by the 
      MM4 T-cell clone. These studies demonstrate directly that expression of alpha4 
      integrin by autoreactive T-cell clones is required for adoptive transfer of EAE 
      in this model. We also define a role for alpha4 integrin in the disease process 
      in mediating the induction and coordinate activation of a matrix 
      metalloproteinase (MMP-2), which facilitates T-cell transmigration.
FAU - Graesser, D
AU  - Graesser D
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut 06510, USA.
FAU - Mahooti, S
AU  - Mahooti S
FAU - Haas, T
AU  - Haas T
FAU - Davis, S
AU  - Davis S
FAU - Clark, R B
AU  - Clark RB
FAU - Madri, J A
AU  - Madri JA
LA  - eng
GR  - R01-HL-51018/HL/NHLBI NIH HHS/United States
GR  - T32-AIO7019/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Antigens, CD)
RN  - 0 (Mmp14 protein, mouse)
RN  - 0 (Protease Inhibitors)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - 143198-26-9 (Integrin alpha4)
RN  - EC 3.4.24.- (Gelatinases)
RN  - EC 3.4.24.- (Matrix Metalloproteinases, Membrane-Associated)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.80 (Matrix Metalloproteinase 14)
SB  - IM
MH  - Animals
MH  - Antigens, CD/*physiology
MH  - Cell Adhesion
MH  - Cell Membrane/metabolism
MH  - Cell Movement/physiology
MH  - Cells, Cultured
MH  - Clone Cells
MH  - Encephalomyelitis, Autoimmune, Experimental/*etiology
MH  - Endothelium, Vascular/cytology
MH  - Gelatinases/antagonists & inhibitors/*physiology
MH  - Integrin alpha4
MH  - Matrix Metalloproteinase 14
MH  - Matrix Metalloproteinase 2
MH  - Matrix Metalloproteinases, Membrane-Associated
MH  - Metalloendopeptidases/antagonists & inhibitors/metabolism/*physiology
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Protease Inhibitors/pharmacology
MH  - T-Lymphocytes/metabolism/physiology
MH  - Tissue Inhibitor of Metalloproteinase-2/metabolism
MH  - Transfection
EDAT- 1998/12/05 00:00
MHDA- 1998/12/05 00:01
CRDT- 1998/12/05 00:00
PHST- 1998/12/05 00:00 [pubmed]
PHST- 1998/12/05 00:01 [medline]
PHST- 1998/12/05 00:00 [entrez]
PST - ppublish
SO  - Lab Invest. 1998 Nov;78(11):1445-58.