Detection of macrophage migration inhibitory factor (MIF) in human cholesteatomas and functional implications of correlations to recurrence status and to expression of matrix metalloproteinases-3/9, retinoic acid receptor-beta, and anti-apoptotic galectin-3.
OBJECTIVE
To investigate whether the expression of the macrophage migration inhibitory factor (MIF) 1) is detectable, 2) changes in relation to recurrence and infection status, and 3) relates to the levels of expression of growth regulators/differentiation markers, including galectin-1, -3, and -8, retinoid acid receptors (RAR)]-alpha, -beta, and -gamma, binding sites for sarcolectin, and invasion markers (cathepsins -B and -D, and matrix metalloproteinases [MMP]-2, -3, and -9) in human cholesteatomas.


METHODS
An analysis of 56 cholesteatomas resected by the same surgeon using canal wall up and canal wall down surgical procedures.


METHODS
The immunohistochemical levels of expression of MIF and the proteases were quantitatively determined (using computer-assisted microscopy) on routine histologic slides by specific antibodies, and statistically correlated to parameters of the other markers determined previously in conjunction with data on apoptosis/proliferation.


RESULTS
MIF expression was detected. It was significantly higher in the epithelium (P =.002) and vessels (P =.04) of the connective tissues (but not in the connective tissue itself) of recurrent as opposed to non-recurrent cholesteatomas. The MIF expression is significantly correlated (P =.006) to the RAR beta expression in non-infected cholesteatomas, and to MMP-3 (P <.01) and anti-apoptotic galectin-3 (P =.01) in infected cholesteatomas. The level of MIF expression was also correlated significantly to MMP-9 (P = 0.003), RAR beta (P <.001), and galectin-8 (P =.003) expression in the cholesteatomas regardless of their infection status.


CONCLUSIONS
MIF expression in human cholesteatomas is related to the levels of biologic aggressiveness reflected in their recurrence status and MMP expression, and to the differentiation status reflected in their galactin and RAR beta expressions. Together with galectin-3, it could cooperate to form an anti-apoptotic feedback loop.
Choufani
G
G
Department of Otolaryngology & Head and Neck Surgery, Erasmus University Hospital, Brussels, Belgium.
Ghanooni
R
R
Decaestecker
C
C
Delbrouck
K
K
Simon
P
P
Schüring
M P
MP
Zick
Y
Y
Hassid
S
S
Gabius
H J
HJ
Kiss
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000943:Antigens, Differentiation / Q000032:analysis*; D001424:Bacterial Infections / Q000150:complications; D002648:Child; D018424:Cholesteatoma, Middle Ear / Q000201:enzymology / Q000276:immunology / Q000382:microbiology / Q000473:pathology* / Q000601:surgery; D005260:Female; D037502:Galectin 3; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008263:Macrophage Migration-Inhibitory Factors / Q000032:analysis*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D019278:Matrix Metalloproteinase 3 / Q000032:analysis*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000032:analysis*; D012008:Recurrence
D000943:Antigens, Differentiation; D037502:Galectin 3; D008263:Macrophage Migration-Inhibitory Factors; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9