Protein kinase D1 mediates synergistic MMP-3 expression induced by TNF-α and bradykinin in human colonic myofibroblasts

Stromal myofibroblasts regulate extracellular matrix components through the secretion of matrix metalloproteinases such as MMP-3. Both myofibroblasts and MMP-3 have been implicated in colonic inflammation and cancer but the regulatory signaling mechanism(s) are unknown. Exposure of the human colonic myofibroblast cell line 18Co to TNF-α and bradykinin induced synergistic MMP-3 mRNA and protein expression, which were blocked by the preferential PKC inhibitors GF109203X and Go6983 and by the MEK inhibitor U0126. Transfection with siRNA targeting PKD1, a known downstream target of both bradykinin and PKC, completely inhibited MMP-3 mRNA and protein expression. Our results imply that TNF-α and bradykinin amplify MMP-3 expression at a transcriptional level through a signaling cascade involving PKC, PKD1, and MEK. PKD1 plays a critical role in the expression of MMP-3 in human colonic myofibroblasts, and may contribute to the pathophysiology underlying colitis-associated cancer.

► Myofibroblasts are a major source of MMP-3 induced by TNF-α and bradykinin.
► MMP-3 production involves the PKC/PKD1 axis and the p42/44 MAPK pathway.
► PKD1 plays a key regulatory role in myofibroblast-mediated MMP-3 production.