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

Objectives: To investigate whether the expression of the macrophage migrati on inhibitory factor (MIF) 1) is detectable, 2) changes in relation to recu rrence 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 fo r sarcolectin, and invasion markers (cathepsins -B and -D, and matrix metal loproteinases [MMP]-2, -3, and -9) in human cholesteatomas. Study Design: A n analysis of 56 cholesteatomas resected by the same surgeon using canal wa ll up and canal wall down surgical procedures. Methods. The immunohistochem ical levels of expression of MIF and the proteases were quantitatively dete rmined (using computer-assisted microscopy) on routine histologic slides by specific antibodies, and statistically correlated to parameters of the oth er markers determined previously in conjunction with data on apoptosis/prol iferation. Results. AUF expression was detected. It was significantly highe r in the epithelium (P = .002) and vessels (P = .04) of the connective tiss ues (but not in the connective tissue itself) of recurrent as opposed to no n-recurrent cholesteatomas. The MIF expression is significantly correlated (P = .006) to the RAR beta expression in noninfected cholesteatomas, and to MMP-3 (P < .01) and anti-apoptotic galectin-3 (P = .01) in infected choles teatomas. The level of MIF expression was also correlated significantly to MMP-9 (P = 0.003), RAR beta (P < .001), and galectin-8 (P = .003) expressio n 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, an d to the differentiation status reflected in their galactin and RAR beta ex pressions. Together with galectin-3, it could cooperate to form an anti-apo ptotic feedback loop.