Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion.
We investigated whether cysteinyl leukotrienes (cysLT) are intracrine signal transducers that regulate human eosinophil degranulation mechanisms. Interleukin (IL)-16, eotaxin, and RANTES stimulate vesicular transport-mediated release of preformed, granule-derived IL-4 and RANTES from eosinophils and the synthesis at intracellular lipid bodies of LTC(4), the dominant 5-lipoxygenase-derived eicosanoid in eosinophils. 5-Lipoxygenase inhibitors blocked IL-16-, eotaxin-, and RANTES-induced IL-4 release; but neither exogenous LTC(4), LTD(4), nor LTE(4) elicited IL-4 release. Only after membrane permeabilization enabled cysLTs to enter eosinophils did LTC(4) and LTD(4) stimulate IL-4, but not RANTES, release. LTC(4)-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known G protein-coupled cysLT receptors (cysLTRs) (CysLT1 and CysLT2) did not block LTC(4)-elicited IL-4 release. LTC(4) was 10-fold more potent than LTD(4) and at low concentrations (0.3-3 nM) elicited, and at higher concentrations (>3 nM) inhibited, IL-4 release from permeabilized eosinophils. Likewise with intact eosinophils, LTC(4) export inhibitors, which increased intracellular LTC(4), inhibited eotaxin-elicited IL-4 release. Thus, LTC(4) acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release. These results demonstrate that LTC(4), well recognized as a paracrine mediator, may also dynamically govern inflammatory and immune responses as an intracrine mediator of eosinophil cytokine secretion.
Bandeira-Melo
Christianne
C
Department of Medicine, Harvard Thorndike Laboratories, Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Woods
Lesley J
LJ
Phoofolo
Mojabeng
M
Weller
Peter F
PF
D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D018946:Chemokine CCL5 / Q000378:metabolism; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D017997:Leukotriene C4 / Q000502:physiology; D017998:Leukotriene D4 / Q000502:physiology; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000502:physiology; D018077:Receptors, Leukotriene / Q000502:physiology*; D022161:Transport Vesicles / Q000502:physiology*
C515350:CCR3 protein, human; D018946:Chemokine CCL5; D008565:Membrane Proteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018077:Receptors, Leukotriene; D015847:Interleukin-4; D017997:Leukotriene C4; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D001094:Arachidonate 5-Lipoxygenase; D019869:Phosphatidylinositol 3-Kinases; C083169:leukotriene D4 receptor