PubMed · 9128067
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M Miyasaka. 1996. [Adhesion molecules].. https://pubmed.ncbi.nlm.nih.gov/9128067/
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Alveolar monocyte influx requires adherence and transmigration through the vascular endothelium, extracellular matrix, and alveolar epithelium. For investigating the monocyte migratory process across the epithelial barrier, we employed both the A549 cell line and isolated human alveolar epithelial cells. Under baseline conditions, spontaneous bidirectional transepithelial monocyte migration was noted, which was dose-dependently increased in the presence of the monocyte chemoattractant protein-1. TNF-alpha stimulation of the alveolar epithelium provoked the polarized apical secretion of monocyte chemoattractant protein-1 and RANTES and up-regulation of ICAM-1 and VCAM-1 expression, accompanied by markedly enhanced transepithelial monocyte traffic in the basal-to-apical direction. Multiple adhesive interactions were noted to contribute to the enhanced monocyte traffic across the TNF-alpha-stimulated alveolar epithelium: these included the beta 2 integrins CD11a, CD11b, CD11c/CD18, the beta 1 integrins very late Ag (VLA)-4, -5, and -6, and the integrin-associated protein CD47 on monocytes, as well as ICAM-1, VCAM-1, CD47, and matrix components on the epithelial side. In contrast, spontaneous monocyte migration through unstimulated epithelium depended predominantly on CD11b/CD18 and CD47, with some additional contribution of VLA-4, -5, and -6. In summary, unlike transendothelial monocyte traffic, for which beta 1 and beta 2 integrins are alternative mechanisms, monocyte migration across the alveolar epithelium largely depends on CD11b/CD18 and CD47 but required the additional engagement of the beta 1 integrins for optimal migration. In response to inflammatory challenge, the alveolar epithelium orchestrates enhanced monocyte traffic to the apical side by polarized chemokine secretion and up-regulation of ICAM-1 and VCAM-1.
Cell adhesion molecule expression (CAM) and IL-8 release in lung microvascular endothelium facilitate neutrophil accumulation in the lung. This study investigated the effects of lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria, alone and with LPS or TNF-alpha, on CAM expression and IL-8 release in human lung microvascular endothelial cells (HLMVEC). The concentration-dependent effects of Staphylococcus aureus (S. aureus) LTA (0.3-30 microg/ml) on ICAM-1 and E-selectin expression and IL-8 release were bell shaped. Streptococcus pyogenes (S. pyogenes) LTA had no effect on CAM expression, but caused a concentration-dependent increase in IL-8 release. S. aureus and S. pyogenes LTA (30 microg/ml) abolished LPS-induced CAM expression, and S. aureus LTA reduced LPS-induced IL-8 release. In contrast, the effects of S. aureus LTA with TNF-alpha on CAM expression and IL-8 release were additive. Inhibitory effects of LTA were not due to decreased HLMVEC viability, as assessed by ethidium homodimer-1 uptake. Changes in neutrophil adhesion to HLMVEC paralleled changes in CAM expression. Using RT-PCR to assess mRNA levels, S. aureus LTA (3 microg/ml) caused a protein synthesis-dependent reduction (75%) in LPS-induced IL-8 mRNA and decreased the IL-8 mRNA half-life from >6 h with LPS to approximately 2 h. These results suggest that mechanisms exist to prevent excessive endothelial cell activation in the presence of high concentrations of bacterial products. However, inhibition of HLMVEC CAM expression and IL-8 release ultimately may contribute to decreased neutrophil accumulation, persistence of bacteria in the lung, and increased severity of infection.
Integrins are major adhesion- and signaling-receptor proteins that mediate cell migration and invasion. They also trigger a variety of signal transduction pathways and regulate cytoskeletal organization, specific gene expression, growth control, and apoptosis (programmed cell death). Consequently, integrins are thought to play important roles in embryonic development and in the biology of cancers. The functions of integrins can be negatively regulated by the recently discovered tumor suppressor PTEN, a protein with homology to protein tyrosine phosphatases and tensin. The PTEN gene is mutated in a wide range of human cancers. PTEN inhibits cell migration and invasion by directly dephosphorylating two key tyrosine-phosphorylated proteins, thereby antagonizing interactions of integrins with the extracellular matrix and integrin-triggered signaling pathways. Other studies demonstrate important roles for PTEN in dephosphorylating a key signal transduction lipid. In the absence of PTEN, this lipid signal transduction pathway can protect tumor cells from apoptosis. Thus, PTEN appears to be a unique tumor suppressor-with both lipid phosphatase and protein tyrosine phosphatase activities-that negatively regulates cell interactions with the extracellular matrix and that maintains cell sensitivity to apoptosis, e.g., after loss of cell contact with the extracellular matrix. The complex signal transduction pathways regulated by PTEN are described in this review. PTEN and the signaling pathways it regulates may provide novel targets for potential therapy.