Intravenous gamma globulin inhibits the production of matrix metalloproteinase-9 in macrophages

Abstract

Background: Degradation of the extracellular matrix (ECM) is essential for progression and metastasis of cancer cells. The ECM-degrading enzymes, matrix metalloproteinases (MMPs), are produced mainly by intratumor monocytes/macrophages. MMPs, particularly MMP-9, are reported to be of crucial significance for both growth and tumor invasiveness. Inhibition of the expression of MMP-9 may prevent tumor development. High-dose intravenous gamma globulins (IVIG) effectively inhibit metastatic spread of tumors in mice and humans and a variety of mechanisms have been suggested to explain this effect.

Methods: We studied the effect of purified IVIG on MMP-9 secretion and mRNA expression by in vitro differentiated human monocytic cells (cell lines and peripheral blood monocytes). Zymography was employed to measure gelatinase secretion and Northern blot analysis was used to detect mRNA expression. Involvement of F(ab)(2) and Fc components in IVIG activity was also evaluated.

Results: IVIG dose dependently and significantly reduced the amount of secreted MMP-9 and its mRNA expression. F(ab)(2), but not Fc fragments, led to suppressed MMP-9 activity. However, competitive experiments demonstrated that Fc, but not F(ab)(2) fragments, reversed the IVIG-induced inhibitory effects.

Conclusions: These results suggest that the whole IgG molecule may be needed for pertinent IVIG-induced MMP-9 down-regulation. This study points to an additional new mechanism whereby IVIG may play a beneficial role in the prevention of tumor spread in humans.