Biological and Molecular Characteristics of Interleukin-5 and its Receptor

Karlen, Stéphane; Ml, De Boer; Rj, Lipscombe; Lutz, W; Mordvinov, Viatcheslav A.; Sanderson, CJ

doi:10.3109/08830189809042996

Cited by 48 publications

(43 citation statements)

References 145 publications

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“…IL-4 and IL-13 may both act as effectors of allergic-type inflammation; IL-13 has often been the more important effector molecule (32). IL-5, a product of TH2 cells, plays an important role in mobilizing eosinophils from the bone marrow (33). Thus, if insulitis were mediated by ''allergic'' inflammatory responses, the absence of TH2 cytokines in IL-4R␣Ϫ͞Ϫ mice could explain the protection of these animals from diabetes.…”

Section: Discussionmentioning

confidence: 99%

A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes

Radu

Noben-Trauth

Hu‐Li

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Autoimmune insulin-dependent diabetes mellitus (IDDM) occurs spontaneously in mice-bearing transgenes encoding the influenza hemagglutinin under the control of the rat insulin promoter and a T cell receptor specific for an hemagglutinin peptide associated with I-E d . Such ''double transgenic'' mice expressing wild-type or targeted IL-4R␣ genes were examined for the onset of IDDM. Eight of 11 mice homozygous for wild-type IL-4R␣ were hyperglycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the targeted allele were hyperglycemic at this time. Most 1L-4R␣؊͞؊ mice remained normoglycemic to 36 weeks of age. Although only 10% of double transgenic mice homozygous for the wild-type IL-4R␣ allele survived to 30 weeks, 80% of mice homozygous for the targeted allele did so. Heterozygous mice displayed an intermediate frequency of diabetes. Even as late as 270 days of age, mice homozygous for the targeted allele had no insulitis or only peri-insulitis. Thus, the inability to respond to IL-4 and͞or IL-13 protects mice against IDDM in this model of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes

Radu

Noben-Trauth

Hu‐Li

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…1 is a T cell-derived cytokine that plays a central role in maturation and proliferation of eosinophils (1). IL5 exerts biological functions through recruitment of a cell surface receptor composed of two polypeptide chains (2), ␣ and ␤.…”

Section: Interleukin 5 (Il5)mentioning

confidence: 99%

“…: 215-762-4197; Fax: 215-762-4452; E-mail: imc23@drexel.edu. 1 The abbreviations used are: IL5, interleukin 5; IL5R␣, interleukin 5 receptor ␣ chain; sIL5R␣, soluble form of IL5R␣; GM-CSF, granulocyte/ macrophage-colony-stimulating factor; CRM, cytokine recognition motif; FnIII, fibronectin type III; RU, resonance unit(s).…”

Section: Interleukin 5 (Il5)mentioning

confidence: 99%

Kinetic Interaction Analysis of Human Interleukin 5 Receptor α Mutants Reveals a Unique Binding Topology and Charge Distribution for Cytokine Recognition

Ishino

Pasut

Scibek

et al. 2004

Journal of Biological Chemistry

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Human interleukin 5 receptor ␣ (IL5R␣) comprises three fibronectin type III domains (D1, D2, and D3) in the extracellular region. Previous results have indicated that residues in the D1D2 domains are crucial for high affinity interaction with human interleukin 5 (IL5). Yet, it is the D2D3 domains that have sequence homology with the classic cytokine recognition motif that is generally assumed to be the minimum cytokinerecognizing unit. In the present study, we used kinetic interaction analysis of alanine-scanning mutational variants of IL5R␣ to define the residues involved in IL5 recognition. Soluble forms of IL5R␣ variants were expressed in S2 cells, selectively captured via their C-terminal V5 tag by anti-V5 tag antibody immobilized onto the sensor chip and examined for IL5 interaction by using a sandwich surface plasmon resonance biosensor method. Marked effects on the interaction kinetics were observed not only in D1 (Asp 55 , Asp 56 , and Glu 58 ) and D2 (Lys 186 and Arg 188 ) domains, but also in the D3 (Arg 297 ) domain. Modeling of the tertiary structure of IL5R␣ indicated that these binding residues fell into two clusters. The first cluster consists of D1 domain residues that form a negatively charged patch, whereas the second cluster consists of residues that form a positively charged patch at the interface of D2 and D3 domains. These results suggest that the IL5⅐IL5R␣ system adopts a unique binding topology, in which the cytokine is recognized by a D2D3 tandem domain combined with a D1 domain, to form an extended cytokine recognition interface. Interleukin 5 (IL5)1 is a T cell-derived cytokine that plays a central role in maturation and proliferation of eosinophils (1). IL5 exerts biological functions through recruitment of a cell surface receptor composed of two polypeptide chains (2), ␣ and ␤. The ␣ chain is IL5-specific and is called IL5 receptor ␣ (IL5R␣), whereas the ␤ chain is shared with IL3 and GM-CSF (3, 4) and is called common ␤ chain (␤c). The ␣ chains for IL3, GM-CSF, and IL5R␣ also share a high degree of amino acid sequence similarity and constitute a distinct subgroup within the cytokine receptor family (5). Because IL5 has been implicated in the pathology of eosinophil-related inflammatory diseases, designing specific antagonists for IL5R␣ may offer therapeutic benefits in the treatment of such diseases (6, 7).IL5 initially binds to IL5R␣ with high affinity, and the resulting complex recruits ␤c to induce cytoplasmic signal transduction. Human IL5R␣ alone binds IL5 with an equilibrium dissociation constant (K d ) of 0.3-0.6 nM when expressed in COS cells (8). The binding affinity is increased only 2-to 5-fold when human ␣ and ␤ chains are co-expressed (3). In other words, IL5R␣ provides most of the IL5 binding energy, whereas ␤c is essentially for signaling. IL5R␣ consists of an extracellular region, a single transmembrane region and a cytoplasmic region. A soluble form of IL5R␣ (sIL5R␣) containing only the extracellular region was cloned and expressed (9). This form has provided a conv...

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“…By mediating eosinophilia, IL5 is involved in the pathogenesis of a number of allergic diseases, most notably asthma (3), rhinitis, and dermatitis (4). Although IL5 is reported to be produced by mast cells and eosinophils, the regulation of eosinophilia is primarily mediated by T-lymphocytes, which produce IL5 after activation (5). Activation of T-cells requires the interaction of the T-cell receptor with antigen, which leads to an increase in intracellular calcium concentration and activation of protein kinase C (6).…”

mentioning

confidence: 99%

“…IL5, like many other cytokines, is regulated at the transcriptional level (5). Although control of IL5 expression is not fully understood, there is increasing evidence that unique mechanisms are involved in activation of the gene.…”

mentioning

confidence: 99%

Specific Activation of Human Interleukin-5 Depends on de Novo Synthesis of an AP-1 Complex

Schwenger

Kok

Arthaningtyas

et al. 2002

Journal of Biological Chemistry

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It is clear from the biology of eosinophilia that a specific regulatory mechanism must exist. Because interleukin-5 (IL5) is the key regulatory cytokine, it follows that a gene-specific control of IL5 expression must exist that differs even from closely related cytokines such as IL4. Two features of IL5 induction make it unique compared with other cytokines; first, induction by cyclic adenosine monophosphate (cAMP), which inhibits other T-cell-derived cytokines, and second, sensitivity to protein synthesis inhibitors, which have no effect on other cytokines. This study has utilized the activation of different transcription factors by different stimuli in a human T-cell line to study the role of conserved lymphokine element 0 (CLE0) in the specific induction of IL5. In unstimulated cells the ubiquitous Oct-1 binds to CLE0. Stimulation induces de novo synthesis of the AP-1 members JunD and Fra-2, which bind to CLE0. The amount of IL5 produced correlates with the production of the AP-1 complex, suggesting a key role in IL5 expression. The formation of the AP-1 complex is essential, but the rate-limiting step is the synthesis of AP-1, especially Fra-2. This provides an explanation for the sensitivity of IL5 to protein synthesis inhibitors and a mechanism for the specific induction of IL5 compared with other cytokines.

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Biological and Molecular Characteristics of Interleukin-5 and its Receptor

Cited by 48 publications

References 145 publications

A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes

A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes

Kinetic Interaction Analysis of Human Interleukin 5 Receptor α Mutants Reveals a Unique Binding Topology and Charge Distribution for Cytokine Recognition

Specific Activation of Human Interleukin-5 Depends on de Novo Synthesis of an AP-1 Complex

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