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Interleukin-5 and IL-5 receptor in health and diseases.

Takatsu K - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Bottom Line: IL-5 is produced by both hematopoietic and non-hematopoietic cells including T cells, granulocytes, and natural helper cells.IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct2.Intravenous administration of humanized anti-IL-5 monoclonal antibody reduces baseline bronchial mucosal eosinophils in mild asthma; providing important implications for strategies that inhibit the actions of IL-5 to treat asthma and other allergic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. takatsuk@med-u-toyama.ac.jp

ABSTRACT
While interleukin-5 (IL-5) is initially identified by its ability to support the growth and terminal differentiation of mouse B cells in vitro into antibody-secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells including B cells, eosinophils, and basophils. IL-5 is produced by both hematopoietic and non-hematopoietic cells including T cells, granulocytes, and natural helper cells. IL-5 exerts its effects for proliferation and differentiation via receptors that comprise an IL-5-specific α and common β-subunit. IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct2. IL-5 signals are transduced through JAK-STAT, Btk, and Ras/Raf-ERK signaling pathways and lead to maintenance of survival and functions of B cells and eosinophils. Overexpression of IL-5 in vivo significantly increases eosinophils and B cells in number, while mice lacking a functional gene for IL-5 or IL-5 receptor display a number of developmental and functional impairments in B cells and eosinophil lineages. In humans, the biologic effects of IL-5 are best characterized for eosinophils. The recent expansion in our understanding of eosinophil development and activation and pathogenesis of eosinophil-dependent inflammatory diseases has led to advance in therapeutic options. Intravenous administration of humanized anti-IL-5 monoclonal antibody reduces baseline bronchial mucosal eosinophils in mild asthma; providing important implications for strategies that inhibit the actions of IL-5 to treat asthma and other allergic diseases.

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Related in: MedlinePlus

Signal transduction through IL-5R. (A) Comparison of amino acid residues among IL-5Rα, IL-3Rα, and GM-CSFRα and their functional domains.41,70) (B) Molecular basis of IL-5 signal transduction in human eosinophils. IL-5 stimulation of eosinophils activates JAK2/STAT5 and Ras–MAP kinase pathways leading to induction of the expression of genes involved in eosinophil growth, survival, and activation.76) Activation of JAK2 is critical for IL-5 signaling. Spred-1 is a negative regulator of Erk activation and regulates IL-5-induced eosinophil activation. (C) IL-5 stimulation of mouse B cells activates three different signaling pathways, namely JAK2/STAT5, Btk, and Ras–MAP kinase leading to induction of the expression of genes involved in B cell proliferation and survival, and differentiation.
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fig09: Signal transduction through IL-5R. (A) Comparison of amino acid residues among IL-5Rα, IL-3Rα, and GM-CSFRα and their functional domains.41,70) (B) Molecular basis of IL-5 signal transduction in human eosinophils. IL-5 stimulation of eosinophils activates JAK2/STAT5 and Ras–MAP kinase pathways leading to induction of the expression of genes involved in eosinophil growth, survival, and activation.76) Activation of JAK2 is critical for IL-5 signaling. Spred-1 is a negative regulator of Erk activation and regulates IL-5-induced eosinophil activation. (C) IL-5 stimulation of mouse B cells activates three different signaling pathways, namely JAK2/STAT5, Btk, and Ras–MAP kinase leading to induction of the expression of genes involved in B cell proliferation and survival, and differentiation.

Mentions: IL-5 stimulation induces rapid tyrosine phosphorylation of cellular proteins including the βc, SH2/SH3-containing proteins such as Vav and Shc, Btk and Btk-associated molecules, JAK1/JAK2 and STAT1/STAT5, PI3K, and MAP kinases that activate downstream signaling molecules76–78,94–101) (Fig. 9). Activation of tyrosine kinases and signal transducer and activator of transcription (STAT) protein plays an indispensable role in the IL-5 signaling. Regarding the negative regulation of IL-5 signaling, STAT5-induced cytokine inducible SH2 protein (CIS) and JAK2-binding SH2-containing protein (JAB, also called SOCS1) play a role in eosinophils, which are one of the feedback loops of IL-5 signaling.96) IL-5 also activates NF-κB in activated B-2 cells and eosinophils, which is dependent on TNFR-associated factor 6 (TRAF6).100) IL-5 enhances the gene expression of c-Myc, c-Fos, c-Jun, Cis, Cish1/Jab, and pim-1 in B cells.77,96) The JAK/c-Myc pathway is indispensable for IL-5-induced cell proliferation and anti-apoptosis, and IL-5-induced up-regulation of c-Myc is dependent upon JAK1 and JAK2 activation.98)


Interleukin-5 and IL-5 receptor in health and diseases.

Takatsu K - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Signal transduction through IL-5R. (A) Comparison of amino acid residues among IL-5Rα, IL-3Rα, and GM-CSFRα and their functional domains.41,70) (B) Molecular basis of IL-5 signal transduction in human eosinophils. IL-5 stimulation of eosinophils activates JAK2/STAT5 and Ras–MAP kinase pathways leading to induction of the expression of genes involved in eosinophil growth, survival, and activation.76) Activation of JAK2 is critical for IL-5 signaling. Spred-1 is a negative regulator of Erk activation and regulates IL-5-induced eosinophil activation. (C) IL-5 stimulation of mouse B cells activates three different signaling pathways, namely JAK2/STAT5, Btk, and Ras–MAP kinase leading to induction of the expression of genes involved in B cell proliferation and survival, and differentiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313690&req=5

fig09: Signal transduction through IL-5R. (A) Comparison of amino acid residues among IL-5Rα, IL-3Rα, and GM-CSFRα and their functional domains.41,70) (B) Molecular basis of IL-5 signal transduction in human eosinophils. IL-5 stimulation of eosinophils activates JAK2/STAT5 and Ras–MAP kinase pathways leading to induction of the expression of genes involved in eosinophil growth, survival, and activation.76) Activation of JAK2 is critical for IL-5 signaling. Spred-1 is a negative regulator of Erk activation and regulates IL-5-induced eosinophil activation. (C) IL-5 stimulation of mouse B cells activates three different signaling pathways, namely JAK2/STAT5, Btk, and Ras–MAP kinase leading to induction of the expression of genes involved in B cell proliferation and survival, and differentiation.
Mentions: IL-5 stimulation induces rapid tyrosine phosphorylation of cellular proteins including the βc, SH2/SH3-containing proteins such as Vav and Shc, Btk and Btk-associated molecules, JAK1/JAK2 and STAT1/STAT5, PI3K, and MAP kinases that activate downstream signaling molecules76–78,94–101) (Fig. 9). Activation of tyrosine kinases and signal transducer and activator of transcription (STAT) protein plays an indispensable role in the IL-5 signaling. Regarding the negative regulation of IL-5 signaling, STAT5-induced cytokine inducible SH2 protein (CIS) and JAK2-binding SH2-containing protein (JAB, also called SOCS1) play a role in eosinophils, which are one of the feedback loops of IL-5 signaling.96) IL-5 also activates NF-κB in activated B-2 cells and eosinophils, which is dependent on TNFR-associated factor 6 (TRAF6).100) IL-5 enhances the gene expression of c-Myc, c-Fos, c-Jun, Cis, Cish1/Jab, and pim-1 in B cells.77,96) The JAK/c-Myc pathway is indispensable for IL-5-induced cell proliferation and anti-apoptosis, and IL-5-induced up-regulation of c-Myc is dependent upon JAK1 and JAK2 activation.98)

Bottom Line: IL-5 is produced by both hematopoietic and non-hematopoietic cells including T cells, granulocytes, and natural helper cells.IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct2.Intravenous administration of humanized anti-IL-5 monoclonal antibody reduces baseline bronchial mucosal eosinophils in mild asthma; providing important implications for strategies that inhibit the actions of IL-5 to treat asthma and other allergic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. takatsuk@med-u-toyama.ac.jp

ABSTRACT
While interleukin-5 (IL-5) is initially identified by its ability to support the growth and terminal differentiation of mouse B cells in vitro into antibody-secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells including B cells, eosinophils, and basophils. IL-5 is produced by both hematopoietic and non-hematopoietic cells including T cells, granulocytes, and natural helper cells. IL-5 exerts its effects for proliferation and differentiation via receptors that comprise an IL-5-specific α and common β-subunit. IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct2. IL-5 signals are transduced through JAK-STAT, Btk, and Ras/Raf-ERK signaling pathways and lead to maintenance of survival and functions of B cells and eosinophils. Overexpression of IL-5 in vivo significantly increases eosinophils and B cells in number, while mice lacking a functional gene for IL-5 or IL-5 receptor display a number of developmental and functional impairments in B cells and eosinophil lineages. In humans, the biologic effects of IL-5 are best characterized for eosinophils. The recent expansion in our understanding of eosinophil development and activation and pathogenesis of eosinophil-dependent inflammatory diseases has led to advance in therapeutic options. Intravenous administration of humanized anti-IL-5 monoclonal antibody reduces baseline bronchial mucosal eosinophils in mild asthma; providing important implications for strategies that inhibit the actions of IL-5 to treat asthma and other allergic diseases.

Show MeSH
Related in: MedlinePlus