016 TNF‐alpha Mediated Induction of MMP‐9 is Modulated by P21‐activated Kinase (PAK)

Abstract

Matrix metalloproteinase‐9 (MMP‐9) transiently expresses in acute wound. In non‐healed wounds, MMP‐9 together with other proteinases persistently elevate, which may lead excessive ECM degradation and failure of wound closure. To understand the molecular regulation of MMP‐9 we investigated the signal transduction for TNF‐alpha mediated induction of MMP‐9 by dermal fibroblasts. TNF‐alpha initiates three major signal pathways including NF‐11B, JUN N‐terminal kinase (JNK), and p38 MAPK. On the other hand, Rho‐GTPase plays an important role in a variety of cellular functions including cell morphogenesis, motility, survival, angiogenesis, and mitosis. It remains unknown if the “cross talk” of these signals having a role in regulation of matrix metalloproteinases (MMPs). In this study we found that over expression of the p21‐activated kinase (PAK) specifically attenuates TNF‐alpha mediated induction of MMP‐9. However, TNF‐alpha mediated induction of MMP‐3 and proMMP‐2 activation was intact. NF‐κB signal is regarded as a common pathway for many MMPs. Indeed, PAK did not affect TNF‐alpha mediated degradation of Ikappa B, suggesting additional signal is targeted by PAK. In contrast, MMP‐3 but not MMP‐9 expression is specifically blocked by p38 MAK. Thus TNF‐alpha induced expression of multiple MMPs in wound healing may utilize different intracellular signal pathways.