Cytokine-induced monocyte MMP-1 is negatively regulated by GSK-3 through a p38 MAPK-mediated decrease in ERK1/2 MAPK activation.

Elucidation of the signal transduction events leading to the production of MMPs by monocytes/macrophages may provide insights into the mechanisms involved in the destruction of connective tissue associated with chronic inflammatory lesions. Here, we show that GSK-3 is a negative regulator of cytokine-induced MMP-1 production by monocytes. Inhibition of monocyte GSK-3 pharmacologically with SB216763 or GSK-3ß siRNA caused a significant enhancement of MMP-1 by TNF-α- and GM-CSF-activated monocytes, indicating that induction of MMP-1 by TNF-α and GM-CSF involved phosphorylation/inactivation of GSK-3. TNF-α- and GM-CSF-induced phosphorylation of GSK-3 and subsequent MMP-1 production was blocked with the PKC inhibitor Gö6976 but not by the AKT1/2 inhibitor AKT VIII, showing that cytokine phosphorylation of GSK-3 occurs primarily through a PKC pathway. Inhibition of GSK-3 resulted in decreased phosphorylation of p38 MAPK with a corresponding increase in phosphorylation of ERK1/2 MAPK. Enhanced MMP-1 production by treatment with SB216763 was a result of increased ERK1/2 activation, as demonstrated by inhibition of MMP-1 by PD98059, a specific ERK1/2 inhibitor. Conversely, the p38 MAPK inhibitor SB203580 enhanced cytokine activation of ERK1/2 and the production of MMP-1 similar to that of SB216763. These findings demonstrate that the degree of cytokine-mediated phosphorylation/inhibition of GSK-3 determines the level of MMP-1 production through a mechanism involving decreased activation of p38 MAPK, a negative regulator of ERK1/2 required for cytokine-induced production of MMP-1 by monocytes.