The Journal of Experimental Medicine
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Published 16 September 2002. doi:10.1084/jem.20020516
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© Rockefeller University Press, 0022-1007/2002/9/841/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 6, September 16, 2002 841-850

Intracrine Cysteinyl Leukotriene Receptor–mediated Signaling of Eosinophil Vesicular Transport–mediated Interleukin-4 Secretion

Christianne Bandeira-Melo, Lesley J. Woods, Mojabeng Phoofolo and Peter F. Weller

Department of Medicine, Harvard Thorndike Laboratories, Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Address correspondence to Peter F. Weller, Beth Israel Deaconess Medical Center, DA-617, 330 Brookline Ave., Boston, MA 02215. Phone: 617-667-3307; Fax: 617-667-5541; E-mail: pweller{at}caregroup.harvard.edu

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 LTC4, the dominant 5-lipoxygenase–derived eicosanoid in eosinophils. 5-Lipoxygenase inhibitors blocked IL-16–, eotaxin-, and RANTES-induced IL-4 release; but neither exogenous LTC4, LTD4, nor LTE4 elicited IL-4 release. Only after membrane permeabilization enabled cysLTs to enter eosinophils did LTC4 and LTD4 stimulate IL-4, but not RANTES, release. LTC4-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 LTC4-elicited IL-4 release. LTC4 was 10-fold more potent than LTD4 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, LTC4 export inhibitors, which increased intracellular LTC4, inhibited eotaxin-elicited IL-4 release. Thus, LTC4 acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release. These results demonstrate that LTC4, well recognized as a paracrine mediator, may also dynamically govern inflammatory and immune responses as an intracrine mediator of eosinophil cytokine secretion.

Key Words: eotaxin • interleukin-16 • RANTES • leukotriene C4 • 5-lipoxygenase


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