Extranuclear Lipid Bodies, Elicited by CCR3-mediated Signaling Pathways, Are the Sites of Chemokine-enhanced Leukotriene C4Production in Eosinophils and Basophils

Christianne Bandeira-Melo, Mojabeng Phoofolo, Peter F. Weller
2001 Journal of Biological Chemistry  
Eosinophils and basophils, when activated, become major sources of cysteinyl leukotrienes, eicosanoid mediators pertinent to allergic inflammation. We show that the C-C chemokines, eotaxin and RANTES (regulated upon activation normal T cell expressed and secreted), activate eosinophils and basophils for enhanced leukotriene C 4 (LTC 4 ) generation by distinct signaling and compartmentalization mechanisms involving the induced formation of new cytoplasmic lipid body organelles. Chemokineinduced
more » ... . Chemokineinduced lipid body formation and enhanced LTC 4 release were both mediated by CCR3 receptor G protein-linked downstream signaling involving activation of phosphoinositide 3-kinase, extracellular signal-regulated kinases 1 and 2, and p38 mitogen-activated protein kinases. Chemokine-elicited lipid body numbers correlated with increased calcium ionophore-stimulated LTC 4 production; and as demonstrated by intracellular immunofluorescent localization of newly formed eicosanoid, lipid bodies were the predominant sites of LTC 4 synthesis in both chemokine-stimulated eosinophils and chemokine-primed and ionophore-activated eosinophils. Eotaxin and RANTES initiated signaling via phosphoinositide 3-kinase and mitogen-activated protein kinases both elicits the formation of lipid body domains and promotes LTC 4 formation at these specific extranuclear sites. Central to the pathogenesis of allergic diseases are both the recruitment and subsequent activation of specific leukocytes, including notably eosinophils and basophils, at sites of allergic inflammation (1-3). Eosinophils and basophils are major potential sources of cysteinyl leukotrienes (LTs) 1 (LTC 4 and its extracellular derivatives, LTD 4 and LTE 4 ), products of the 5-lipoxygenase (5-LO) pathway of arachidonic metabolism (4). Cysteinyl LTs, as paracrine mediators, cause bronchoconstriction, mucous hypersecretion, increased microvascular permeability, bronchial hyperresponsiveness, and eosinophil infiltration (5-7) and, as autocrine mediators,
doi:10.1074/jbc.m101436200 pmid:11274187 fatcat:jnfmhblbnfdlxjcmaf72sixgrm