Role of JAK2 signal transductional pathway in activation and survival of human peripheral eosinophils by interferon-gamma (IFN-γ)

Abstract

The purpose of this study was to determine whether the JAK pathway is involved in eosinophil activation and survival through IFN-gamma receptor signalling in human peripheral eosinophils. Eosinophils were purified from the blood of six atopic disease patients by anti-CD16 magnetic bead-negative selection. IFN-gamma significantly up-regulated survival and CD69 expression in 24-48 h cultured eosinophils. Further, IFN-gamma induced tyrosine phosphorylation of JAK2 in eosinophils, as indicated by Western blot analysis. Finally, the specific JAK2 inhibitor AG-490 inhibited the tyrosine phosphorylation of JAK2, IFN-gamma-induced survival and CD69 expression in eosinophils. In conclusion, these results indicate that IFN-gamma induces eosinophil survival and CD69 expression through the activation of JAK2 in peripheral eosinophils, suggesting that JAK2 may play a significant role in eosinophil regulation by IFN-gamma-IFN-gammaR interaction.

IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism

“…For instance, JAK2-deficient cells are still responsive to IL-6 (67), but fail completely to respond to IFN-␥, indicating a critical, nonredundant role of JAK2 in the IFN-␥-signaling pathway. In light of our observations that IL-6 failed to induce HMGB1 release and that a specific inhibitor of JAK2, AG490 (69,70), abrogated IFN-␥-induced FIGURE 7. Conceptual relationships between IFN-␥, JAK2, TNF, and HMGB1 release in macrophage cultures.…”

The Role of STAT1 in Activation of IL-3- and IL-5-Induced Eosinophils by Interferon Gamma

“…IFN-γ has been shown to prolong peripheral eosinophil survival [4]and to induce CD69 on cultured peripheral eosinophils, one of the eosinophil activation markers [8]. We have reported that binding of IFN-γ to peripheral eosinophils initiated a series of events that resulted in the rapid tyrosine phosphorylation of not only the IFN-γRα chain but also JAK1, JAK2 and STAT1α [2, 3].…”

“…We have also shown that induction of CD69 expression on peripheral eosinophils by IFN-γ depends on tyrosine phosphorylation of JAK2, using a specific inhibitor, AG-490 [4]. Although there is no specific inhibitor against tyrosine phosphorylation of STAT1α, Lee and Benveniste [5]showed that STAT1α was involved in IFN-γ induction of the class II transactivator and class II MHC gene using an antisense oligonucleotide against STAT1α.…”

Regulation of CD69 Expression on Eosinophil Precursors by Interferon-γ

“…Indeed a specific JAK2 inhibitor, AG490 [15], has been shown to block the anti-apoptotic effect of IFN-γ on peripheral eosinophils [16, 17]. We have previously found that AG-490 could significantly inhibit IL-5- or IFN-γ-induced CD69 expression on peripheral eosinophils [7]. In the present study, we showed that AG-490 could also inhibit the induction of CD69 expression and the tyrosine phosphorylation of JAK2 in eosinophil precursors.…”

“…We have also recently shown that induction of CD69 expression on eosinophils by IFN-γ and prolongation of cell survival depend on tyrosine phosphorylation of JAK2 [7]. On the contrary, we found that IFN-γ inhibits IL-3- and IL-5-induced eosinophil differentiation from progenitor cells [8].…”