Plasminogen (Plg) facilitates inflammatory cell recruitment, a function that depends upon its binding to Plg receptors (Plg-Rs). However, the Plg-Rs that are critical for cell migration are not well defined. Three previously characterized Plg-Rs (␣-enolase, annexin 2, and p11) and a recently identified Plg-R (histone H2B [H2B]) were assessed for their contribution to Plg binding and function on macrophages. Two murine macrophage cell lines (RAW 264.7 and J774A.1) and mouse peritoneal macrophages induced by thioglycollate were analyzed. All 4 Plg-Rs were present on the surface of these cells and showed enhanced expression on the thioglycollate-induced macrophages compared with peripheral blood monocytes. Using blocking Fab fragments to each Plg-R, H2B supported approximately 50% of the Plg binding capacity, whereas the other Plg-Rs contributed less than 25%. Anti-H2B Fab also demonstrated a major role of this Plg-R in plasmin generation and matrix invasion. When mice were treated intravenously with anti-H2B Fab, peritoneal macrophage recruitment in response to thioglycollate was reduced by approximately 45% at 24, 48, and 72 hours, with no effect on blood monocyte levels. Taken together, these data suggest that multiple Plg-Rs do contribute to Plg binding to macrophages, and among these, H2B plays a very prominent and functionally important role.
Background: Macrophage polarization regulates human inflammatory disorders. Results: KLF6 is a novel transcriptional regulator of macrophage polarization. Conclusion: KLF6 regulates macrophage inflammatory gene expression by modulating functions of NF-B and PPAR␥. Significance: Pharmacological agents that modulate KLF6 signaling may allow for therapeutic gain in the treatment of inflammatory disorders.
We have recently reported that osteopontin (OPN) induces nuclear factor B (NFB)-mediated promatrix metalloproteinase-2 activation through IB␣/IKK signaling pathways and that curcumin (diferulolylmethane) down-regulates these pathways (Philip, S., and Kundu, G. C. SN-50) reduced the OPN-induced uPA secretion, cell motility, and invasion. To our knowledge, this is first report that OPN induces NFB activity and uPA secretion by activating PI 3-kinase/ Akt/IKK-mediated signaling pathways and further demonstrates a functional molecular link between OPN-induced PI 3-kinase-dependent Akt phosphorylation and NFB-mediated uPA secretion, and all of these ultimately control the motility of breast cancer cells.Cell migration and extracellular matrix invasion are two of the major steps in embryonic development (1, 2) and wound healing and cancer cell metastasis (3, 4). However, the exact molecular mechanisms that regulate these processes are not well defined. In the past several investigators have shown that urokinase type plasminogen activator (uPA) 1 plays a major role in the regulation of cancer cell motility, extracellular matrix (ECM) invasion, and metastasis by degrading the ECM proteins (5-7). Current investigations have focused on the understanding of molecular mechanism(s) by which osteopontin (OPN), an ECM protein, regulates uPA secretion and controls motility in human breast cancer cells.
Key Points
Plasminogen influences uptake of apoptotic bodies and immunoglobulin-coated red cells by macrophages in mice. Plasminogen regulates expression of genes involved in macrophage phagocytosis in vivo.
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