Meprin-ß regulates production of pro-inflammatory factors via a disintegrin and metalloproteinase-10 (ADAM-10) dependent pathway in macrophages.

ABSTRACT

Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as atherosclerosis. Meprin, an astacin metalloproteinase, has exhibited proinflammatory effects in vivo and in vitro studies. Here, we tried to further investigate the proinflammatory potential of meprin-ß and the possible underlying mechanisms in primary human peripheral blood macrophages. In our current study, ELISA assay revealed that meprin-ß increased the production of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), interleukin-18 and interleukin-6 (IL-6) in macrophages. However, meprin-ß shows no effects on the level of ligands of epidermal growth factor receptor (EGFR), and the activation of EGFR. The molecular mechanism was associated with activation of a disintegrin and metalloproteinase 10 (ADAM10) and the phosphorylation of IκB. Further analysis of upstream mechanisms showed that activation of NF-κB by meprin-ß was mediated by inhibiting ADAM10-downstream extracellular signal regulated kinase (ERK1/2) pathway. Taken together, these results indicated that meprin-ß exhibited pro-inflammatory effects by targeting activating ADAM10, leading to ERK1/2-mediated activation of NF-κB in macrophages, and this would make meprin-ß a strong candidate for further study as proinflammatory target.