cAMP Signaling in Leukocyte Transendothelial Migration

Abstract

Abstract-The migration of leukocytes across the vascular endothelium is crucial for immunosurveillance as well as for inflammatory responses. Uncontrolled leukocyte transendothelial migration results in pathologies such as asthma, rheumatoid arthritis, and atherosclerosis. The molecular mechanisms that regulate leukocyte transendothelial migration involve signaling downstream of intracellular messengers such as cAMP, calcium, phosphoinositol lipids, or reactive oxygen species. Among these, cAMP is particularly intriguing because it is generated in both leukocytes and endothelial cells and regulates leukocyte chemotaxis as well as endothelial barrier function. In addition, physiological stimuli that induce cAMP production generate both pro-and antiinflammatory signals, underscoring the complexity of cAMP-driven signaling. This review discusses our current knowledge of the control of leukocyte transendothelial migration by two main cAMP effectors: protein kinase A and the Rap exchange factor Epac (Exchange protein directly activated by cAMP).

Extracellular Matrix of Glioblastoma Inhibits Polarization and Transmigration of T Cells: The Role of Tenascin-C in Immune Suppression

“…It is likely that PKA and PI3K are important components of the migration machine but are controlled separately by other integrin signals. Migration-controlling kinases recruited to the leading front of migrating lymphocytes can facilitate actin polymerization (17,18,37). In agreement with these findings, the confocal images showed that phosphorylated ERK partly colocalized with actin on the leading edge of Jurkat cells.…”

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

“…Therefore, it seems that cAMP plays a major role in eosinophil migration toward eotaxin per se in agreement with the differential roles that cAMP plays in the complex process of leukocyte migration, depending on the subcellular localization of cAMP production and the relative expression level of different cAMP effectors such as PKA or Epac-1 (exchange protein directly activated by cAMP 1). As recently reviewed by Lorenowicz et al (44), activation of PKA results in inhibition of cell surface expression of selectins and integrins and integrin activation, thereby resulting in reduced adhesion; but PKA is necessary for the clustering of integrins, which is a prerequisite for stable, sustained adhesion. Furthermore, PKA inhibits RhoA, a critical regulator of actin-based contractility.…”

Molecular Biology of Atherosclerosis

“…LTB 4 is clearly chemotactic for neutrophils and macrophages, in part by reducing cAMP levels in migrating cells, similar to chemokines. Of note, elevation of cAMP by various agents inhibits cell migration generally, apparently by PKA phosphorylation of MLCK with a reduction in myosin light-chain phosphorylation and other actions to inhibit lamellipodia formation and extension (292,1076). Other inflammation-amplifying effects of LTB 4 were recently demonstrated in the setting of intermittent hypoxia (1031).…”