Meprin-alpha metalloproteases enhance lipopolysaccharide-stimulated production of tumour necrosis factor-alpha and interleukin-1beta in peripheral blood mononuclear cells via activation of NF-kappaB.

Lipopolysaccharide (LPS) induces the expression of a wide range of pro-inflammatory mediators via NF-kappaB activation. These pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), may be important in triggering atherogenesis. We have previously observed that actinonin, a meprin inhibitor, suppressed the formation of atherosclerotic plaques and, in in vitro experiments, actinonin also had an effect on the way LPS altered THP-1 cell function. The aim of the present study was to investigate whether meprin-alpha regulates LPS-induced production of TNF-alpha and IL-1beta in peripheral blood mononuclear cells (PBMCs) and its potential mechanisms of action. We observed that meprin-alpha could enhance LPS-induced expression of TNF-alpha and IL-1beta mRNA and protein in a time- and concentration-dependent manner, assessed using real-time PCR and ELISA. Meprin-alpha also significantly increased LPS-induced NF-kappaB transcriptional activity. Furthermore, we assessed the effects of meprin-alpha specific siRNA on the production of TNF-alpha and IL-1beta to examine whether meprin-alpha was involved in the process of LPS-induced activation of PBMCs. Our results show that LPS-induced IL-1beta and TNF-alpha production by PBMCs was significantly reversed by meprin-alpha specific siRNA. In addition, the augmentation of meprin-alpha of the LPS-induced expression of TNF-alpha and IL-1beta was significantly decreased by Bay-117082, an inhibitor of NF-kappaB. In conclusion, our data indicate that meprin-alpha is capable of increasing LPS-induced production of cytokines in peripheral blood mononuclear cells, which might be associated with the activation of NF-kappaB.