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.

Submental intubation is a simple technique associated with a low morbidity. It is an attractive alternative to tracheotomy in the surgical management of selected cases of maxillofacial trauma.

Neutrophils, an abundant cell type at sites of inflammation, have the ability to produce a number of cytokines, including interleukin 1 (IL-1), IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha). In this study, we have examined the ability of human neutrophils to produce the IL-1 receptor antagonist (IL-1Ra), a 17-23-kD protein recently isolated and cloned from macrophages. Since IL-1Ra has been shown to inhibit both the in vitro and in vivo effects of IL-1, its production by large numbers of tissue-invading neutrophils might provide a mechanism by which the effects of IL-1 are regulated in inflammation. Using antibodies that are specific for IL-1Ra and a cDNA probe encoding for this protein, we were able to show that neutrophils constitutively produce IL-1Ra. However, after activation by GM-CSF and TNF-alpha, IL-1Ra was secreted into the extracellular milieu where it constituted the major de novo synthesized product of activated neutrophils. None of a large array of other potent neutrophil agonists were found to affect the production of IL-1Ra by neutrophils. Quantitative measurements by enzyme-linked immunosorbent assay revealed that intracellular IL-1Ra is in eightfold excess of the amount secreted in supernatants when studying nonactivated neutrophils. However, in GM-CSF- and TNF-alpha-activated cells, this difference was reduced to values between four- and fivefold, as virtually all of the de novo synthesized IL-1Ra was secreted. In activated cells, the intracellular content of IL-1Ra was found to be in the 2-2.5-ng/ml range per 10(6) neutrophils, whereas levels reached the 0.5-ng/ml range in supernatants. This would imply that IL-1Ra is produced in excess of IL-1 by a factor of at least 100, an observation that is in agreement with the reported amounts of IL-1Ra needed to inhibit the proinflammatory effects of IL-1. Neutrophils isolated from an inflammatory milieu, the synovial fluid of patients with rheumatoid arthritis, were found to respond to GM-CSF and TNF-alpha in terms of IL-1Ra synthesis, indicating that the in vitro observations made in this study are likely to occur in an inflammatory setting in vivo.

Interleukin-4 (IL-4) and IL-13 are cytokines that share many biological activities. We have previously demonstrated that IL-13 affects a number of neutrophil responses, and here we extend our observations to IL-4. We present, for the first time, direct evidence for the presence of functional IL-4 receptors on human neutrophils. We report that IL-4 induces RNA synthesis in a concentration-dependent manner and, based on observations of the induction of morphological cell shape changes and spreading onto glass, we demonstrate that IL-4 activates neutrophil cytoskeletal rearrangements. We further show that IL-4 is a potent activator of de novo protein synthesis in neutrophils, and we identify by microsequencing one of these proteins as the cytoskeletal protein actin. We were also able to demonstrate for the first time that actin is cleaved into at least two fragments of approximately 30 kDa (pI 5.4) and approximately 25 kDa (pI 5.0) in neutrophils. Finally, we report that IL-4 delays neutrophil apoptosis, as assessed by morphological observations from cytocentrifuge preparations, as well as by measurement of differences in staining by flow cytometry with both propidium iodide and Hoechst reagent. Taken together, we conclude that IL-4 is a more potent neutrophil agonist than previously believed. We discuss the possibility that the induction of the de novo synthesis of actin by IL-4 is related to the mechanism by which this cytokine delays apoptosis; in addition, the cleavage of this protein is likely to contribute to the apoptotic process.