IL-12 regulates an endothelial cell-lymphocyte network: effect on metalloproteinase-9 production.
IL-12 is key cytokine in innate immunity and participates in tumor rejection by stimulating an IFN-gamma-mediated response characterized by CD8(+) mediated-cytotoxicity, inhibition of angiogenesis, and vascular injury. We previously demonstrated that activated lymphocytes stimulated with IL-12 induced an angiostatic program in cocultured vascular endothelial cells. In this study, we have extended this observation showing that a reciprocal modulation of cellular responses occurs. Actually, the presence of endothelial cells enhanced the inhibitory effect of IL-12 on metalloproteinase-9 expression in activated PBMC as well as their ability to transmigrate across an extracellular matrix. IL-12 triggered intracellular signaling, as indicated by STAT-1 activation, appeared to mainly operative in activated CD4 (+) cells challenged with IL-12, but it was also initiated in CD8(+) lymphocytes in the presence of endothelial cells. On the other hand, stimulated PBMC reduced the expression and the activity of metalloproteinase-9, up-regulated that of tissue inhibitor metalloproteinase-1, and stimulated the STAT-1 pathway in cocultured endothelial cells. We used neutralizing Abs to show that the IFN-inducible protein 10 (CXCL10) and monokine-induced by IFN-gamma (CXCL9) chemokines produced by both PBMC and endothelial cells are pivotal in inducing these effects. Altogether these results suggest the existence of an IL-12-regulated circuit between endothelium and lymphocytes resulting in a shift of proteolytic homeostasis at site of tissue injury.
D001485:Basement Membrane / Q000201:enzymology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D005109:Extracellular Matrix / Q000201:enzymology / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis
C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D020780:Matrix Metalloproteinase 9