Synergistic Effects of Interleukin-4 or Interleukin-13 and Tumor Necrosis Factor- α on Eosinophil ActivationIn Vitro

Abstract

Increased concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4, and IL-13 have been measured in bronchoalveolar lavage fluid (BALF) of patients with asthma following allergen provocation. In addition, these cytokines have also been reported to activate eosinophils in vitro. Although cytokine interactions have been postulated in the activation of eosinophils, the combined effects of cytokines on eosinophil activation remain poorly understood. Because activation of eosinophils has been regarded as a crucial event in the pathogenesis of asthmatic inflammation, we tested the hypothesis that IL-4 and IL-13 could enhance the effects of TNF-alpha on eosinophil activation. For this purpose, eosinophils from normal donors were purified and cultured in the presence of IL-4 or IL-13 and TNF-alpha. Eosinophil survival and surface expression of CD69 were assessed by flow cytometry. There was a concentration- and time-dependent upregulation in CD69 expression as well as eosinophil survival when eosinophils were incubated with IL-13, IL-4, or TNF-alpha. However, eosinophil viability and CD69 expression increased synergistically when eosinophils were incubated with IL-13 or IL-4 in the presence of TNF-alpha. This synergistic effect of IL-4 and IL-13 on CD69 expression was not limited to TNF-alpha but was also observed with IL-5. Our study provides evidence that IL-4 can activate eosinophils in a similar fashion as does IL-13. Furthermore, this study shows that the addition of IL-4 or IL-13 to TNF-alpha or IL-5 has synergistic effects on eosinophil activation, suggesting that the combined effects of different cytokines present in BALF following allergen provocation can enhance eosinophil activation in vitro.

The Respiratory Syncytial Virus Fusion Protein and Neutrophils Mediate the Airway Mucin Response to Pathogenic Respiratory Syncytial Virus Infection

“…Increased concentrations of TNF-␣ and IL-13 have been measured in the BAL fluid of asthmatic patients following allergen stimulation (66). In a model of allergic asthma, IL-13 instillation results in TNF-␣ expression by neutrophils (67) and is necessary for mucus production (68).…”

BLT2 Is Upregulated in Allergen-Stimulated Mast Cells and Mediates the Synthesis of Th2 Cytokines

“…IL-4 and IL-13 are key cytokines in the pathogenesis of asthma (3-5, 42, 43). Expression of IL-4 in the lungs of IL-4 TG mice elicits an inflammatory response characterized by epithelial cell hypertrophy, accumulation of macrophages, lymphocytes, eosinophils, and neutrophils, and an AHR response to inhaled methacholine (3,42). Similarly, chronic pulmonary overexpression of IL-13 in mouse lungs results in a complex phenotype characterized by an eosinophil inflammatory response, goblet cell hyperplasia, and subepithelial fibrosis (4,43).…”

“…Cross-linking of cell surface IgE bound to FcεRI by Ag leads to the rapid release of inflammatory mediators, including histamine, proteases, arachidonic acid metabolites, and various cytokines (2). Th2 cytokines (e.g., IL-4 and IL-13) produced by mast cells regulate important inflammatory responses in asthma (3)(4)(5). Despite the important role of mast cells in the synthesis of Th2 cytokines, the signaling mechanism by which Ag stimulation mediates Th2 cytokine production in mast cells is not well understood.…”

Endothelial cells modulate eosinophil surface markers and mediator release

“…CD69 may be a coreceptor for eosinophil activation, or, as for platelets and monocytes, facilitate mediator release or degranulation [9,36,37]. CD69 is barely detectable on freshly isolated eosinophils but is rapidly expressed after stimulation with numerous cytokines [9,[38][39][40]. CD69 is also present on bronchoalveolar lavage eosinophils [8,9,34].…”