Abstract. Leukocyte-derived proteases have long been considered simply degradative. However, emerging data raise possibilities of a complex and specific biologic role for these proteases in substrate processing and in signaling pathways within cells. This study reports that the release of neutrophilic and monocytic proteases, such as proteinase 3 (PR3) and human neutrophil elastase (HNE), can result in their entry into endothelial cells coincident with the activation of proapoptoticsignaling events through ERK, JNK, and p38 MAPK. Inhibition of JNK blocked PR3-induced apoptosis, and inhibition of p38 MAPK blocked PR3-and HNE-induced apoptosis, indicating that these pathways are required for activation of apoptosis. It is here shown that protease entry results in direct cleavage of p65 NF-B in the N-terminal region by PR3 and in the C-terminal region by HNE. This cleavage results in diminished transcriptional activity by NF-B as demonstrated by diminished levels of TNF-␣-induced IL-8 message in the presence of PR3 or HNE. Inhibition of caspases did not block the cleavage of p65 NF-B, and sequence analysis showed that the PR3 and HNE cleavage sites are unique with respect to reported caspase sites. The data demonstrate that PR3 and HNE have specific, fundamental roles in endothelial responses during inflammation. Upon entry, they can usurp the cell's control of its own fate by directly intervening into caspase cascades. This provides a unique mechanism of crosstalk between leukocytes and endothelial cells at sites of inflammation that impacts both cytokine networks and cell viability.
Methotrexate (MTX) is an antimetabolite, folic acid antagonist that inhibits purine nucleotide production, DNA synthesis, and cellular proliferation. Despite widespread therapeutic uses, MTX remains a potent teratogen. Methotrexate embryopathy encompasses multiorgan system dysfunction, including intrauterine growth restriction as well as cardiac, craniofacial, renal, genital, and skeletal abnormalities. Effects of MTX exposure on fetal development continue to be described. This series of 4 patients with MTX-associated craniosynostosis represents the largest published association between prenatal MTX exposure and premature cranial suture closure.
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