Proinflammatory activation of human macrophages by the serine protease plasmin. Characterization of signaling pathways
LicenseStandard (Fassung vom 01.10.2008)
This study demonstrates that macrophages express higher amounts of the annexin A2 heterotetramer compared to monocytes. Activation of macrophages by plasmin leads to cleavage of the annexin A2 subunit of the receptor, followed by activation of JAK1 signaling, which results in STAT3 activation, Akt-dependent NF-kappaB activation, and phosphorylation of MAPK p38 and ERK1/2. Moreover, the plasmin-induced activation of STAT3 and p65/NF-kappaB transcription factors and their translocation to the nucleus and binding to the corresponding response DNA sequences, trigger expression and release of the proinflammatory cytokines TNF-alpha and IL-6. Pharmacological inhibitors of JAK, p38 and NF-kappsB revealed that these signaling pathways are indispensable for the plasmin-mediated expression of the TNF-alpha and IL-6 genes. By contrast, the ERK1/2 activation is essential only for the expression of IL-6 gene. The observed MIP-3alpha release is dependent on p38 activation.Furthermore, at the molecular level activation of macrophages depends on the proteolytic activity of plasmin as shown by the use of plasmin that had been catalytically inactivated by the specific chloromethyl ketone VPLCK. Plasmin activated macrophages via a receptor composed of annexin A2 and S100A10, so-called annexin A2 heterotetramer. Plasmin initiates signaling in monocytes by proteolytic cleavage of the annexin A2 subunit of the receptor, generation of the N-terminal peptide of annexin A2 and the dissociation of the annexin A2 heterotetramer. The N-terminal peptide of annexin A2 is able to mimic the plasmin-induced activation of the tyrosine kinase JAK1 and the transcriptional factor STAT3 as well as the expression of CCL2/MCP-1. Activation of this pathway may require a new member of the type I cytokine receptor, IL31Ralpha. Consistently, down-regulation of the expression of IL31Ralpha, but not of gp130, impairs the plasmin-induced activation of human monocytes.
Subject HeadingsPlasmin [GND]