The mechanism of IL-5 signal transduction

Abstract

Cytokines are important regulators of hematopoiesis. They exert their actions by binding to specific receptors on the cell surface. Interleukin-5 (IL-5) is a critical cytokine that regulates the growth, activation, and survival of eosinophils. Because eosinophils play a seminal role in the pathogenesis of asthma and allergic diseases, an understanding of the signal transduction mechanism of IL-5 is of paramount importance. The IL-5 receptor is a heterodimer of α- and β-subunits. The α-subunit is specific, whereas the β-subunit is common to IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) receptors and is crucial for signal transduction. It has been shown that there are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2 tyrosine kinases and SHP-2 tyrosine phosphatase are important for eosinophil survival. In contrast to their survival-promoting activity, Lyn and JAK2 appear to have no role in eosinophil degranulation or expression of surface adhesion molecules. Raf-1 kinase, on the other hand, is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5 stimulation of B cell function. However, it does not appear to be important for eosinophil function. Thus a clear segregation of signaling molecules based on their functional importance is emerging. This review describes the signal transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and compares and contrasts IL-5 signaling between eosinophils and B cells.

IL-5 Up-Regulates Cysteinyl Leukotriene 1 Receptor Expression in HL-60 Cells Differentiated into Eosinophils

“…Signaling through IL-5R␣/IL-5R␤ leads to activation of Janus kinase 2 and subsequent phosphorylation and dimerization of STAT factors. IL-5 also activates Lyn, Syk, Raf-1, and PI3 kinases and SHP-2 tyrosine phosphatase, which are differentially involved in eosinophil growth and differentiation, survival, up-regulation of adhesion molecules or priming for degranulation, and production of superoxide and LTC 4 (51). The eventual involvement of these signaling molecules in the observed up-regulation of CysLT 1 R by IL-5 remains to be elucidated.…”

Eosinophilia predicts better overall survival after acute graft-versus-host-disease

“…24,25 These observations provide an explanation for the possible protective role of Th2 cytokines in acute GVHD. IL-5 is another Th2 cytokine that has a crucial role in the proliferation, differentiation, survival and activation of eosinophils, 1,14,26 and the CD4 þ Th2 cells are known to produce large amounts of IL-5. Therefore, as speculated in the previous study, 8 we speculate that eosinophilia after allogeneic HSCT may reflect activation of Th2 cells, resulting in higher production of Th2 cytokines, less severe GVHD and better outcomes.…”

Upregulated response to chemokines in oxidative metabolism of eosinophils in asthma and allergic rhinitis

“…Interestingly, no augmentative effect of GM-CSF was demonstrated despite the b subunit (bc) being common to both IL-5 and GM-CSF receptors. Although bc plays a major role in IL-5 signalling [24], recent evidence indicates that the specific IL-5 receptor IL-5Ra is also involved in signal transduction. GEIJSEN et al [25] have cloned an IL-5Ra-associated molecule, syntenin, which is required for activation of the transcription factor Sox4.…”