Molecular Characterization and Functional Analysis of Murine Interleukin 4 Receptor Allotypes

Schulte, Tim; Kurrle, R.; Röllinghoff, Martin; Gessner, André

doi:10.1084/jem.186.9.1419

Cited by 38 publications

(40 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The specificity of this assay was convincingly demonstrated by the fact that s␥c was undetectable in sera and in cell culture supernatants of ␥c Ϫ/Ϫ mice. The constitutive concentration of s␥c in the sera of immunocompetent mice (more than 200 ng/ mL) was 10-to more than 100-fold higher than those reported previously for the soluble forms of the IL-4R (1-2 ng/mL), 44 IL-6R (less than 10 ng/mL), 48 or the tumor necrosis factor receptors (TNF-Rs; p55 60 pg/mL, p75 5 ng/mL), 49 respectively.…”

Section: Discussionmentioning

confidence: 72%

“…Iodinated s␥c was repurified by the use of an anti-␥c affinity column. Equilibrium binding of 125 I-s␥c to murine IL-4R expressed on human TF-1 cells 44 was measured after the incubation of 2 ϫ 10 6 cells in the presence of 125 I-s␥c and 100 ng/mL IL-4, in a final volume of 200 L in microfuge tubes at 4°C for 120 minutes. To separate nonbound 125 I-s␥c from cell-bound 125 I-s␥c, the reaction mixture was centrifuged through an oil gradient.…”

Section: Sodium Iodide I 125-s␥c-binding Assaysmentioning

confidence: 99%

“…It has been shown 47 by surface plasmon resonance that the extracellular domain of the ␥c binds to a preformed binary IL-4R/IL-4 complex, but not to immobilized IL-4R or IL-4 alone. Thus, affinity-purified s␥c was labeled with 125 I and added together with saturating concentrations of IL-4 to transfected TF-1 cells, 44 expressing approximately 20 000 molecules of the mouse IL-4R␣ per cell. As depicted in Figure 7C, 125 I-s␥c bound to the cells in a specific manner because binding competition was seen with excess of the wild-type s␥c (255 N-Stop-s␥c).…”

Section: Org Frommentioning

confidence: 99%

“…To separate nonbound 125 I-s␥c from cell-bound 125 I-s␥c, the reaction mixture was centrifuged through an oil gradient. 44 Specificity of binding was determined by the addition of a 200-fold excess of unlabeled s␥c.…”

Section: Sodium Iodide I 125-s␥c-binding Assaysmentioning

confidence: 99%

See 3 more Smart Citations

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Meißner

Blum

Schnare

et al. 2001

Blood

View full text Add to dashboard Cite

The common gamma-chain (␥c) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble ␥c (s␥c) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the fulllength ␥c showed that shedding of the transmembrane receptor led to the release of s␥c. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence s␥c release. In vivo, superantigen-induced stimulation of T cells enhanced s␥c serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of s␥c. A physiological role of s␥c was indicated by its capacity to specifically inhibit cell growth induced by ␥c-dependent cytokines. Mutational analysis revealed that the Cterminus and the WSKWS motif are essential for the cytokine inhibitory effect of the s␥c and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane ␥c by excess s␥c is the most likely mechanism of cell growth inhibition. It was implied that naturally produced s␥c is a negative modulator of ␥c-dependent cytokines. IntroductionThe murine common gamma-chain (␥c) is a 64-kd type 1 transmembrane protein of the cytokine receptor family. 1 Although the ␥c alone is unable to bind to cytokines, it has been shown to be an essential component of the cell surface receptor complexes of IL-2, IL-4, IL-7, IL-9, and IL-15. 1 Interaction of the respective cytokines with the ␥c within the receptor complexes results in the activation of the Janus kinase JAK3, 2 which subsequently interacts with Pyk2, a member of focal adhesion tyrosine kinases, leading to the phosphorylation of this protein. 3 Recent studies have shown that the ␥c is critical for lymphoid development because genetic defects of either this molecule 4 or JAK3 5 in humans or targeted deletions of the ␥c 6,7 or JAK3 8-10 in mice severely impair the development of T and B cells, leading to severe combined immune deficiency syndromes (SCID). 11 Soluble cytokine receptors and growth factor receptors are present as immunomodulatory molecules in body fluids of humans and mice (reviewed in references 12 and 14). Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] ...

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Sodium Iodide I 125-s␥c-binding Assaysmentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

Section: Sodium Iodide I 125-s␥c-binding Assaysmentioning

confidence: 99%

See 2 more Smart Citations

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Meißner

Blum

Schnare

et al. 2001

Blood

View full text Add to dashboard Cite

show abstract

“…25 However, the BALB/c variant of IL-4Ra exhibits amino-acid substitutions, which result in less avid ligand binding and more rapid ligand dissociation, compared to the B6 variant. 26 As a result, the B6 IL-4Ra genotype is associated with an enhanced IL-4 secretion phenotype, 25 in contrast to Tsi1, where the BALB/c genotype confers increased IL-4 secretion. It is therefore unlikely that IL-4ra gives rise to the linkage we detect at Tsi1.…”

Section: Discussionmentioning

confidence: 99%

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Choi

Rose

et al. 2005

Genes Immun

View full text Add to dashboard Cite

Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation

et al. 2011

View full text Add to dashboard Cite

Mammalian interleukin-4 (IL-4) and IL-13 are T helper type 2 (Th2) cytokines with pleiotropic functions in immunity. They signal through receptors containing IL-4Rα and IL-2Rγ or IL-13Rα1. In addition, a decoy receptor, IL-13Rα2, is known to exist and modulates the function of IL-13. The existence of fish orthologues to mammalian IL-4 and IL-13 is still under debate. However, the receptor chains have been predicted in zebrafish, and we have previously cloned IL-2Rγ and IL-13Rα2 in rainbow trout. In this study, we have cloned a further five novel trout IL-4/13 receptors. Thus, each of the IL-4Rα, IL-13Rα1 and IL-13Rα2 chains has two copies. The identities of the receptors is supported by homology analysis, characteristic domain structure, phylogenetic tree analysis and synteny analysis in zebrafish. However, the characteristic WSXWS motif of structural importance in mammalian type I cytokine receptors is missing in all fish IL-4Rα and IL-13Rα1 molecules. All the receptors have a characteristic domain structure that is similar to their mammalian counterparts except for IL-13Rα1b that has the N-terminal Ig domain missing. Since this Ig domain is a specific and critical binding unit for IL-13 but not for IL-4 signalling, its absence potentially converts the IL-13Rα1b into a receptor that can only signal via IL-4 ligation. The existence of duplicated receptor genes perhaps suggests that more ligands still remain to be discovered that will bind these receptors. The duplicated receptors are differentially expressed in most tissues and cell lines examined, and their expression can be modulated by LPS, polyIC and IFN-γ in cell lines. In contrast, the T-cell stimulant phytohaemagglutinin increased the expression of IL-4Rα1 and IL-4Rα2, but not IL-13Rα1/2, suggesting a role of an IL-4-like molecule in T-cell growth/activation in fish.

show abstract

Molecular Characterization and Functional Analysis of Murine Interleukin 4 Receptor Allotypes

Cited by 38 publications

References 51 publications

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation

Contact Info

Product

Resources

About