Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Rα chain

Abstract

Interleukin-15 (IL-15) is a cytokine that possesses interesting, potential therapeutic properties. However, based on several parameters including activation of neutrophils, it is also recognized as a proinflammatory cytokine. The mechanisms by which IL-15 activates human neutrophil functions are not fully understood. Although these cells express a functional IL-15 receptor (IL-15R) composed of IL-15Ralpha, IL-2/15Rbeta (CD122), and gamma(c) (CD132) subunits, the role of each receptor component has not been investigated in IL-15-induced human neutrophil responses. In the present study, fluorescein-activated cell sorter analysis revealed that the ability of IL-15 to enhance neutrophil phagocytosis is not a result of increased expression of IL-15Ralpha, CD122, or CD132 on the neutrophil cell surface. Pretreatment of neutrophils with specific antibodies to IL-15Ralpha, CD122, or CD132 was found to inhibit phagocytosis of opsonized-sheep red blood cells by nearly 40%, 21%, and 27%, respectively. As expected, pretreatment of neutrophils with anti-IL-2Ralpha (CD25) had no effect. Pretreatment of cells with the Syk inhibitor piceatannol was found to significantly inhibit the ability of IL-15 to enhance phagocytosis. In addition, IL-15 was found to induce tyrosine phosphorylation of Syk that was largely inhibited by pretreating cells with piceatannol. Moreover, we found that Syk kinase is physically associated with IL-15Ralpha. We conclude that IL-15R enhances neutrophil phagocytosis by a Syk-dependent mechanism and that the IL-15Ralpha chain plays a key role in mediating this response, at least by interacting with Syk kinase.

IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival

“…IL-15 and IL-2 share the IL-2R␤-chain, which elicits three main signaling pathways: JAK-STAT, MAPK, and PI3K (25). In addition, there is also a report of involvement of the tyrosine kinase syk in IL-15R signaling (26). The JAK-STAT pathway is critical to the common ␥-chain family of cytokines and would not confer specificity.…”

IL-4Rα, a New Member that Associates with Syk Kinase: Implication in IL-4-Induced Human Neutrophil Functions

“…4B). As expected, each of the inhibitors did not alter the basal level of phagocytosis when tested alone (9,27). To further support a role of Syk, the other inhibitor (Syk inhibitor II) has been tested and the results are (n ϭ 4): 22.5% Ϯ 1.2 (Ctrl), 37.7% Ϯ 4.4 (IL-4), 17.7% Ϯ 3.8 (IL-4 plus inhibitor), and 16.2% Ϯ 6.7 (inhibitor alone).…”

“…Thus, in addition to IL-15R␣ (9), IL-4R␣ is another receptor component to which Syk is associated in human PMNs. Of note, in hematopoietic cells, association of Syk with receptor components of CD132-dependent cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and (20) IL-21, is presently limited to IL-2R␤ (20,30), IL-15R␣ (9,20), and now IL-4R␣ (this report). Unlike previous studies, in which the importance of the association of Syk with IL-2R␤ and IL-15R␣ has been reported but not clarified, we present in this study clear evidence that the association of Syk with IL-4R␣ is involved not only in cell signaling, but also in the regulation of major neutrophil functions such as apoptosis, phagocytosis, and adhesion.…”

“…Moreover, it has recently become clear that IL-4 produced in inflamed tissues can activate signaling events in normal resident cells of the airway (38). Interestingly, both IL-4 and IL-15 cytokines activate Syk in human PMNs (2,3,6,7,9) and enhance phagocytosis and adhesion, two important biological processes involved during inflammation. Although the biological activities of these two cytokines appear to be redundant in PMNs, this does not rule out the possibility that major differences will be reported in future.…”

“…Although the cell signaling events involved in IL-4-induced PMNs are not fully understood, we have recently documented that IL-4 recruits the Jak-STAT-SOCS and MAPK pathways and that it activates Syk in these cells (2) as well as in promyelocytic leukemia PLB-985 cells (8). Recently, IL-15 was found to enhance human PMN phagocytosis by a Sykdependent mechanism and the importance of the IL-15R␣-chain in IL-15-induced PMNs has been demonstrated (9).…”