MODULATION OF MMP-2 (GELATINASE-A) AND MMP-9 (GELATINASE-B) BY INTERFERON-GAMMA IN A HUMAN SALIVARY-GLAND CELL-LINE

Gelatinases have been shown to be regulated by many cytokines and grow th factors, and have been implicated in the pathogenesis of certain au toimmune diseases via tissue destruction. High levels of several cytok ines, including IFN-gamma and TNF-alpha, have been demonstrated in the salivary gland microenvironment of patients with Sjogren's syndrome ( SS). How these cytokines may be contributing to the pathogenesis of th is disease is not well understood We hypothesized that IFN-gamma with or without (+/-) TNF-alpha could be playing a role in the pathogenesis of SS via the regulation of matrix metalloproteinase (MMP) levels. Th is study examined the role of IFN-gamma (+) TNF-alpha in the regulatio n of the matrix metalloproteinases, MMP-2 (72 kD gelatinase A) and MMP -9 (92 kD gelatinase B). A human salivary gland cell line (HSG) has be en used as a possible in vitro model to study the role of IFN-gamma TNF-alpha. in the pathogenesis of SS. The HSG cell line, in the presen ce of IFN +/- TNF-alpha, displays increased MMP-2 and MMP-9 gelatinoly tic activity, protein and RNA levels. The increase in MMP activity was partially blocked with an antibody against the IFN-gamma receptor, an d this was associated with a complete inhibition of the previously des cribed IFN-gamma +/- TNF-alpha antiproliferative effect. However, incu bation of IFN-gamma treated HSG cells with the synthetic MMP inhibitor BB94 did not alleviate this antiproliferative effect. In addition, we demonstrate that there are very high levels of MMP-9 In the saliva of patients with SS when compared to healthy control subjects. These dat a suggest that cytokines could be regulating MMP production by salivar y epithelial cells and thus indicate a potential role for these cells in the pathogenesis of SS. (C) 1997 Wiley-Liss, Inc.