Interactions of T helper cells with fibroblast-like synoviocytes: up-regulation of matrix metalloproteinases by macrophage migration inhibitory factor from both Th1 and Th2 cells.
OBJECTIVE
Interactions of immune cells, such as activated T helper cells, with fibroblast-like synoviocytes (FLS) play a crucial role in the joint destruction during human rheumatoid arthritis (RA). This study was undertaken to investigate the expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) by T helper cells, and to assess the role of MIF in overexpression of matrix metalloproteinases (MMPs) in cocultures of FLS from arthritic mice with either Th1 or Th2 cells.


METHODS
MIF expression by in vitro-polarized murine Th1 and Th2 cells was determined using 2 different generation protocols. FLS were isolated from the inflamed joints of mice with antigen-induced arthritis. MMP expression was analyzed in cocultures of the FLS with T helper cell subsets. Effects of MIF were blocked by a neutralizing anti-MIF antibody. In addition, analyses were performed on cocultures of either Th1 or Th2 cells with FLS from MIF-deficient mice.


RESULTS
Both Th1 and Th2 cells expressed high quantities of MIF. MMPs were overexpressed by FLS after coculture with both Th1 and Th2 cells. Activated T helper cells were more effective than resting cells. Neutralization of MIF by an anti-MIF antibody led to a marked reduction in MMP expression in Th1- and Th2-stimulated FLS. T helper cells generated from MIF-deficient mice exhibited a T helper cell-specific cytokine profile comparable with that in wild-type cells, except in the expression of MIF, but showed an impaired ability to stimulate MMP expression in FLS.


CONCLUSIONS
MIF is an important Th1 and Th2 cell-derived proinflammatory cytokine that stimulates MMP expression in FLS from arthritic mice, and therefore inhibition of MIF might be a promising target for novel therapeutic strategies in human RA.
Schurigt
Uta
U
University Hospital Jena, Jena, Germany. uta.schurigt@uni-wuerzburg.de
Pfirschke
Christina
C
Irmler
Ingo M
IM
Hückel
Marion
M
Gajda
Mieczyslaw
M
Janik
Tobias
T
Baumgrass
Ria
R
Bernhagen
Jürgen
J
Bräuer
Rolf
R
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism / Q000502:physiology; D007719:Knee Joint / Q000276:immunology / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D013583:Synovial Membrane / Q000166:cytology; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D015854:Up-Regulation
D008263:Macrophage Migration-Inhibitory Factors; D020782:Matrix Metalloproteinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse