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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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IL-5 binding and chemical crosslinking of IL-5 binding protein. (A) IL-5 binding assay shows existence of the low- and high affinity IL-5 receptor on IL-5 responsive B cell lines.63) (B) Chemical crosslinking of IL-5 binding protein from B cell lines. Crosslinking studies using 3SS-labeled IL-5 detected 160 kDa and 92.5 kDa band under high-affinity conditions, while only 92.5 kDa bands were detected under low-affinity conditions.63) (C) Inhibitory effects of anti-IL-5R mAb (H7 and R52) and anti-IL-3R mAb (Aic-2B) on IL-5-induced DNA synthesis of IL-5-dependent Y16 cells.67) (D) Schematic illustration of IL-5 receptor complex. Details are described in the text.
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fig03: IL-5 binding and chemical crosslinking of IL-5 binding protein. (A) IL-5 binding assay shows existence of the low- and high affinity IL-5 receptor on IL-5 responsive B cell lines.63) (B) Chemical crosslinking of IL-5 binding protein from B cell lines. Crosslinking studies using 3SS-labeled IL-5 detected 160 kDa and 92.5 kDa band under high-affinity conditions, while only 92.5 kDa bands were detected under low-affinity conditions.63) (C) Inhibitory effects of anti-IL-5R mAb (H7 and R52) and anti-IL-3R mAb (Aic-2B) on IL-5-induced DNA synthesis of IL-5-dependent Y16 cells.67) (D) Schematic illustration of IL-5 receptor complex. Details are described in the text.

Mentions: IL-5 acts on target cells by binding to its specific IL-5 receptor (IL-5R). In mice, IL-5 responsive B cells and eosinophils express small numbers (approximately 50) of high-affinity IL-5R (Kd of 10–150 pM) and large numbers (around 1,000) of low-affinity IL-5R (Kd of 2–10 nM)62,63) (Fig. 3A). Biological responsiveness to mIL-5 depends on interaction with the high affinity IL-5R. Chemical crosslinking studies of mIL-5R with IL-5 reveal that the high affinity mIL-5R consists of two distinct subunits, α and β (Fig. 3B).63) IL-5 specifically binds to the IL-5Rα subunit. We developed anti-IL-5Rα mAb, H7 that could recognize 60 kDa proteins on IL-5-responsive cells and specifically inhibit IL-5-dependent cell proliferation.64,65) Rolink and his colleagues propagated another mIL-5R mAb, R52.120, which partially inhibited IL-5-induced cell proliferation and recognized 130 kDa proteins.66) Interestingly, addition of H7 and R51.120 mAbs to the cell culture completely inhibited IL-5-induced proliferation (Fig. 3C).67) As anti-IL-3R mAb, Aic2B showed similar inhibitory activity to that of R52.120, we speculated that H7 and R52.120 could recognize IL-5Rα and IL-5Rβ subunit, respectively (Fig. 3D).


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

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

IL-5 binding and chemical crosslinking of IL-5 binding protein. (A) IL-5 binding assay shows existence of the low- and high affinity IL-5 receptor on IL-5 responsive B cell lines.63) (B) Chemical crosslinking of IL-5 binding protein from B cell lines. Crosslinking studies using 3SS-labeled IL-5 detected 160 kDa and 92.5 kDa band under high-affinity conditions, while only 92.5 kDa bands were detected under low-affinity conditions.63) (C) Inhibitory effects of anti-IL-5R mAb (H7 and R52) and anti-IL-3R mAb (Aic-2B) on IL-5-induced DNA synthesis of IL-5-dependent Y16 cells.67) (D) Schematic illustration of IL-5 receptor complex. Details are described in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: IL-5 binding and chemical crosslinking of IL-5 binding protein. (A) IL-5 binding assay shows existence of the low- and high affinity IL-5 receptor on IL-5 responsive B cell lines.63) (B) Chemical crosslinking of IL-5 binding protein from B cell lines. Crosslinking studies using 3SS-labeled IL-5 detected 160 kDa and 92.5 kDa band under high-affinity conditions, while only 92.5 kDa bands were detected under low-affinity conditions.63) (C) Inhibitory effects of anti-IL-5R mAb (H7 and R52) and anti-IL-3R mAb (Aic-2B) on IL-5-induced DNA synthesis of IL-5-dependent Y16 cells.67) (D) Schematic illustration of IL-5 receptor complex. Details are described in the text.
Mentions: IL-5 acts on target cells by binding to its specific IL-5 receptor (IL-5R). In mice, IL-5 responsive B cells and eosinophils express small numbers (approximately 50) of high-affinity IL-5R (Kd of 10–150 pM) and large numbers (around 1,000) of low-affinity IL-5R (Kd of 2–10 nM)62,63) (Fig. 3A). Biological responsiveness to mIL-5 depends on interaction with the high affinity IL-5R. Chemical crosslinking studies of mIL-5R with IL-5 reveal that the high affinity mIL-5R consists of two distinct subunits, α and β (Fig. 3B).63) IL-5 specifically binds to the IL-5Rα subunit. We developed anti-IL-5Rα mAb, H7 that could recognize 60 kDa proteins on IL-5-responsive cells and specifically inhibit IL-5-dependent cell proliferation.64,65) Rolink and his colleagues propagated another mIL-5R mAb, R52.120, which partially inhibited IL-5-induced cell proliferation and recognized 130 kDa proteins.66) Interestingly, addition of H7 and R51.120 mAbs to the cell culture completely inhibited IL-5-induced proliferation (Fig. 3C).67) As anti-IL-3R mAb, Aic2B showed similar inhibitory activity to that of R52.120, we speculated that H7 and R52.120 could recognize IL-5Rα and IL-5Rβ subunit, respectively (Fig. 3D).

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