The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the Ras-Raf-1-MEK-microtubule-associated protein kinase pathway.

Abstract

SummaryInterleukin 5 (IL-5) regulates the growth and function of eosinophils. The objective of this study was to investigate the intraceUular signal transduction mechanism of IL-5 in eosinophils. Purified eosinophils were stimulated with IL-5, and the involvement of various kinases was investigated by immunoblotting, immune complex kinase assay, and in situ denatured/renatured kinase assay. We found that IL-5 induced tyrosine phosphorylation and activation of a number of kinases. Two species of lyn kinases (53 and 56 kD) were present in eosinophils. Both forms were Tyrphosphorylated and activated rapidly within 1 min. Further, lyn kinase was physically associated with the IL-53 receptor in eosinophils. Ras was studied by immunoprecipitation followed by thin-layer chromatography. Ras bound higher quantities of [ot-32p]guanosine 5'-triphosphate upon stimulation with IL-5. Raf-1 kinase showed increased Tyr phosphorylation on immunoblotting and increased activity in the immune complex kinase assay. Two species of MEK (MAP or Erk kinase) (41 and 45 kD) were identified in eosinophils, which underwent autophosphorylation upon stimulation. Microtubule-associated protein (MAP) kinase (p44) was Tyr-phosphorylated on immunoblotting and had increased activity in the immune-complex kinase assay. MAP kinases were also studied after metabolic radiolabeling of the cells with [32p]orthophosphates. IL-5 stimulated phosphorylation of MAP kinases in situ. Thus, we have delineated major components of an important signaling pathway in eosinophils. We believe that one of the signals generated by IL-5 receptor activation is propagated through the lyn-Ras-Raf-I-MEK-MAP kinase pathway.

Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

“…Indeed, TGF b 2 stimulates acute and chronic activation of the MAPK cascade in rat mesangial cells (Huwiler et al, 1994), and TGF b activates Ras and ERK2 in epithelial cells (Hartsough and Mulder, 1995). On the contrary, TGF b inhibits the tyrosine phosphorylation of multiple proteins, among which ERK2, in interleukin 5-treated eosinophils (Pazdrak et al, 1995). It is noteworthy that a member of the MAPKKK family, namely TAK1, has been isolated and shown to mediate TGF b signal transduction (Yamaguchi et al, 1995).…”

Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects

“…ϩ Statistically significant difference between PAF and the vehicle; *Statistically significant differences caused by pretreatment with tyrosine kinase inhibitors. a rapid and reversible tyrosine phosphorylation of various eosinophil proteins [26][27][28][29]. Differential signaling by these related cytokines has been shown.…”

Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils

“…The best established intracellular signaling pathway for βc signals is the one initiated by activating Jak protein kinases followed by tyrosine phosphorylation and activation of the transcription factors STAT5s that induce transcription of a variety of cytokine-inducible genes 11 . It is also known that βc cytokines activate various other signaling molecules including the kinase Syk (A000040) [12][13][14] . Syk and its related kinase Zap70 (A002396) were, on the other hand, well known to be critical for signal transduction by various immunoreceptors, such as lymphocyte antigen receptors and Fc receptors for IgE (FcεRI) and IgG (FcγRs) 15 .…”