Involvement of the α/β Isoform of p38 MAP Kinase in Chemotactic Responses of Human Eosinophils to Eotaxin (CCL11) and RANTES (CCL5)

Anwar M Hasan,Gordon Dent

doi:10.3844/ajisp.2017.209.215

Abstract

Eosinophils are the principal effector cells for allergic inflammation in a variety of diseases, in which they contribute to tissue damage and remodelling processes via the secretion of cytotoxic granular proteins and cytokines. The intracellular mechanisms that control the activation, recruitment and survival of eosinophils are fundamental in understanding these disease processes. Phosphoinositide 3-kinase (PI3K) has been shown previously to be essential for eosinophil chemotactic responses to some stimuli but not others. Human blood neutrophils have been shown to utilize two antagonistic signalling pathways for chemotaxis: PI3K and p38 mitogen-activated protein kinase (p38 MAPK). In the present study, the role of p38 MAPK in chemotactic responses of an eosinophil-differentiated myeloid leukaemia cell line (EOL-1) and human peripheral blood eosinophils to a range of stimuli - platelet-activating factor (PAF), eotaxin 1 (CCL11), RANTES (CCL5), interleukin 8 (IL8, CXCL8) and IL16 - was explored through the use of the p38 MAPK α/β isoform inhibitor, SB 203580. SB 203580 caused significant inhibition of chemotactic responses of both EOL-1 cells and blood eosinophils to eotaxin 1 and RANTES (≥75% inhibition at 1 μM SB 203580, p<0.01) but had no effect on the migration induced by PAF and IL16 (<25%) and little or no effect on responses to IL8. Responses to PAF - but not eotaxin - have been shown previously to be suppressed by PI3K inhibition. The complementary pattern of inhibition observed in the present study provides evidence that distinct PI3K-dependent and p38 MAPK-dependent chemoattractants may also exist for eosinophils.

Highlights

Eosinophils are initiator and effector cells of Th2mediated immunity (Ravin and Loy, 2016)
The complementary pattern of inhibition observed in the present study provides evidence that distinct Phosphoinositide 3-kinase (PI3K)-dependent and p38 MAP kinase (MAPK)-dependent chemoattractants may exist for eosinophils
A range of inflammatory mediators and cytokines have been identified as eosinophil attractants and activators, including plateletactivating factor, CC chemokines including eotaxin (CCL11) (Mishra et al, 2005) and regulated on activation normal T-cell expressed and secreted (RANTES, CCL5) (Svensson et al, 2009), CXC chemokines including interleukin 8 (IL8, CXCL8) (Bates et al, 2010) and the lymphocyte chemoattractant factor interleukin 16 (IL16)

Summary

Introduction

Eosinophils are initiator and effector cells of Th2mediated immunity (Ravin and Loy, 2016). They are associated with key components of inflammation in a variety of chronic diseases affecting the airways (Eng and DeFelice, 2016), heart (Séguéla et al, 2015) and gastrointestinal system (Hogan et al, 2013). A range of inflammatory mediators and cytokines have been identified as eosinophil attractants and activators, including plateletactivating factor, CC chemokines including eotaxin (CCL11) (Mishra et al, 2005) and regulated on activation normal T-cell expressed and secreted (RANTES, CCL5) (Svensson et al, 2009), CXC chemokines including interleukin 8 (IL8, CXCL8) (Bates et al, 2010) and the lymphocyte chemoattractant factor interleukin 16 (IL16)

Methods

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Discussion

Conclusion