IL-16 promotes leukotriene C(4) and IL-4 release from human eosinophils via CD4- and autocrine CCR3-chemokine-mediated signaling.
Human eosinophils are potential sources of inflammatory and immunomodulatory mediators, including cysteinyl leukotrienes, chemokines, and cytokines, which are pertinent to allergic inflammation. We evaluated the means by which IL-16, a recognized eosinophil chemoattractant, might act on eosinophils to affect their capacity to release leukotriene C(4) (LTC(4)) or their preformed stores of chemokines (eotaxin, RANTES) or Th1 (IL-12) or Th2 (IL-4) cytokines. IL-16 dose dependently (0.01-100 nM) elicited new lipid body formation, intracellular LTC(4) formation at lipid bodies, and priming for enhanced calcium ionophore-activated LTC(4) release. IL-16 also elicited brefeldin A-inhibitable, vesicular transport-mediated release of preformed IL-4, but not IL-12, from eosinophils. CD4 is a recognized IL-16R, and accordingly anti-CD4 Fab, soluble CD4, and a CD4 domain 4-based IL-16 blocking peptide inhibited the actions of IL-16 on eosinophils. Although CD4 is not G-protein coupled, pertussis toxin inhibited IL-16-induced eosinophil activation. IL-16 actions were found to be mediated by the autocrine activity, not of platelet-activating factor, but rather of endogenous CCR3-acting chemokines. IL-16 induced the rapid vesicular transport-mediated release of RANTES. The effects of IL-16 were blocked by CCR3 inhibitors (met-RANTES, anti-CCR3 mAb) and by neutralizing anti-eotaxin and anti-RANTES mAbs, but not by platelet-activating factor receptor antagonists (CV6209, BN52021). RANTES and eotaxin each enhanced LTC(4) and IL-4 (but not IL-12) release. Therefore, IL-16 activation of eosinophils is CD4-mediated to elicit the extracellular release of preformed RANTES and eotaxin, which then in an autocrine fashion act on plasma membrane CCR3 receptors to stimulate both enhanced LTC(4) production and the preferential release of IL-4, but not IL-12, from within eosinophils.
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.
Sugiyama
Kumiya
K
Woods
Lesley J
LJ
Phoofolo
Mojabeng
M
Center
David M
DM
Cruikshank
William W
WW
Weller
Peter F
PF
D019898:Autocrine Communication; D020126:Brefeldin A / Q000494:pharmacology; D015704:CD4 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000502:physiology; D019742:Chemokines, CC / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D019410:Interleukin-16 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis*; D017997:Leukotriene C4 / Q000096:biosynthesis*; D008055:Lipids / Q000032:analysis; D037342:Pertussis Toxin; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D022142:Secretory Vesicles / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C515456:CCL11 protein, human; C515350:CCR3 protein, human; D015704:CD4 Antigens; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019410:Interleukin-16; D008055:Lipids; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D010566:Virulence Factors, Bordetella; D018664:Interleukin-12; D020126:Brefeldin A; D015847:Interleukin-4; D017997:Leukotriene C4; D037342:Pertussis Toxin