Signal transduction mechanisms regulating the activation, adhesion and migration of human eosinophils and T-lymphocytes in allergic inflammation

We have investigated the intracellular signal transduction mechanisms for TNF-α, IL-3, IL-5, and GM-CSF-induced expression of adhesion molecules, adhesion and chemotaxis of human eosinophils. TNF-α was found to activate both p38 MAPK and NF-κB signaling pathways in an in vitro model of eosinophils, eosinophilic leukemia, EoL-1 cells. TNF-α-induced surface expression of intercellular adhesion molecule (ICAM)-1 could be inhibited by a proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132) but not a specific p38 MAPK inhibitor (SB 203580) in both human peripheral blood eosinophils and EoL-1 cells. Therefore, TNF-α-induced ICAM-1 expression was through the activation of NF-κB pathway which is independent to the activity of p38 MAPK in eosinophils.; IL-3, IL-5 and GM-CSF, could also activate both p38 MAPK and NF-κB signaling pathways in human eosinophils. These cytokines could induce both surface and gene expressions of several adhesion molecules including ICAM-1 and CD18 on eosinophils. The cytokine-induced surface expression of ICAM-1 involved both p38 MAPK and NF-κB activities, whereas the surface expressions of CD18, CD 11b and ICAM-3 were regulated through p38 MAPK but not NF-κB signaling pathway. Furthermore, both p38 MAPK and NF-κB could regulate the IL-3-, IL-5- and GM-CSF-induced chemotaxis and adhesion of eosinophils. Interaction of eosinophils between bronchial epithelial cells could induce the release of cytokines which could be differentially regulated by p38 MAPK and NF-κB signaling pathways. We found that IL-6, TNF-α, IL-8 and monocyte chemoattractant protein (MCP)-1 were significantly increased in the co-cultures of eosinophils and epithelial cells.; On the other hand, elevated plasma levels of thymus and activation-regulated chemokine (TARC) and soluble cytotoxic T-lymphocyte-associated molecule (CTLA)-4 were found in children with both chronic stable and acute asthma. The plasma levels of both parameters were significantly decreased after systemic corticosteroid treatments.; Based on the above findings, we suggested that IL-3, IL-5, GM-CSF, and TNF-α as well as p38 MAPK and NF-κB signaling pathways play a critical role in regulating the adhesion and migration of eosinophils in inflammatory reactions. TARC and sCTLA-4 may be useful in monitoring the disease severity and therapeutic efficacy of asthmatic children with acute attacks. They are important regulators for T-lymphocyte recruitment and activation.