TNF-α-Dependent ICAM-1- and VCAM-1-Mediated Inflammatory Responses Are Delayed in Neonatal Mice Infected with Pneumocystis carinii

Abstract

Neonatal mice have a delayed CD4-mediated inflammatory response to Pneumocystis carinii (PC) infection in the lungs that corresponds to a delayed TNF-α response and a delayed clearance of the organisms compared with adult mice. Since TNF-α is known to drive the up-regulation of adhesion molecules, we examined the expression and function of adhesion molecules in the lungs of neonatal mice. The expression of both ICAM-1 and VCAM-1 was significantly lower in the lungs of PC-infected neonatal mice compared with adults. Additionally, migration of neonatal T cells across endothelial cells expressing VCAM-1 and monocyte chemotactic protein-1 was aberrant compared with that in adult T cells, although α4β1 integrin-mediated adhesion of neonatal lymphocytes was comparable to that of adult lymphocytes. Treatment of neonatal mice with exogenous TNF-α resulted in increased expression of ICAM-1 and VCAM-1 as well as increased expression of chemokines, resulting in infiltration of CD4+ cells into the lungs. Treatment with exogenous TNF-α resulted in a trend (although not statistically significant) toward a reduction of PC organisms from the lungs. These data indicate that neonatal lung endothelial cells do not up-regulate ICAM-1 and VCAM-1 in response to PC infection, probably due to depressed TNF-α production. Additionally, neonatal T cells are defective in the ability to migrate across endothelial cells.

TNF-α-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells

“…Induced expression of adhesion molecules, especially ICAM-1 and VCAM-1, have been reported to be associated with airway inflammatory responses (Ito et al, 2003;Lee et al, 2003;Qureshi et al, 2003). And, our previous study suggested a potential role of a PKCδ-p38 kinase-VCAM-1-linked cascade in the TNF-α-induced leukocyte adhesion and migration in the lung airway epithelium (Woo et al, 2005).…”

Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species

“…4 Spleen cell migration is stimulated by mHEV cell secretion of the chemokine monocyte chemoattractant protein 1 (MCP-1). 15 The number of lymphocytes that migrate is linear from 0 to 24 hours followed by a plateau. 4 Spleen cells that migrate are more than 95% lymphocytes, 4 and the percentage of cells that migrate is consistent with other in vitro models with endothelial cell lines or cytokine-activated microvascular endothelial cells.…”

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

“…Migration was initiated by the addition of murine splenic lymphocytes (ϳ4 ϫ 10 6 cells) and erythrocytes (ϳ4 ϫ 10 6 cells; nonmigratory control), to the upper chamber of the transwell (29). Chemotaxis is induced by the constitutive expression of MCP-1 by the endothelial cell lines (31). Bile pigments and vehicle were present in both the upper and lower chambers throughout the duration of the experiment.…”