Differential effects of interleukin-15 (IL-15) and IL-2 on human neutrophils: modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15.
Human neutrophils have been shown recently to express both the beta and the gamma chains of the interleukin-2 receptor (IL-2R). IL-15, a cytokine that has recently been cloned and characterized, was found to share many of the biological functions of IL-2 and is known to mediate signals through IL-2R beta and IL-2R gamma. In recent studies, we observed that IL-2 exerts few effects on various neutrophil functions, but information on IL-15-neutrophil interactions is lacking. In this study, we observed that IL-15, in contrast to IL-2, induces important morphological cell shape changes that are typical of activated neutrophils. Furthermore, phagocytosis of opsonized sheep red blood cells was significantly increased by IL-15 but not by IL-2. However, similar to IL-2, IL-15 did not modulate the oxidative burst response. Furthermore, we observed that de novo RNA synthesis is increased in neutrophils by IL-15 along with de novo protein synthesis, whereas no significant effect of IL-2 was noted. Among the different proteins that were found to be upregulated by IL-15, one was identified by microsequencing as the cytoskeletal protein actin. Finally, we found that IL-15 delays apoptosis of neutrophils more efficiently than IL-2 when evaluated by both microscopic observations and flow cytometry procedures. Furthermore, this phenomenon was dose-dependent (10 to 500 ng/mL), and, at 500 ng/mL, IL-15 delayed apoptosis as strongly as granulocyte-macrophage colony-stimulating factor. This study is the first to show that IL-15 is a significant neutrophil agonist. Moreover, in view of the differential effects of IL-15 and IL-2 on this cell type, our results support the existence of a specific IL-15R component(s) on human neutrophils.
Girard
D
D
Arthritis and Inflammation Research Laboratory, Centre de Recherche du Centre Hospitalier de L'Université Laval, Ste-Foy, Québec, Canada.
Paquet
M E
ME
Paquin
R
R
Beaulieu
A D
AD
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects
D000199:Actins; D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4