A recombinant extracellular domain of the human interleukin 4 receptor inhibits the biological effects of interleukin 4 on T and B lymphocytes

Garrone, Pierre; Djossou, Odile; Galizzi, Jean‐Pierre; Banchereau, Jacques

doi:10.1002/eji.1830210606

Cited by 59 publications

(25 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Concentrations effecting half-maximal responses (EC 50 values) were reported to range from 0.5 to 200 pM (e.g. Garrone et al, 1991;Rigley et al, 1991;Kruse et al, 1992). The IL-4 activities are mediated by a receptor system for which up to now only a single protein has been identified.…”

mentioning

confidence: 99%

Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation.

et al. 1993

View full text Add to dashboard Cite

Interleukin 4 (IL‐4) exerts a decisive role in the coordination of protective immune responses against parasites, particularly helminths. A disregulation of IL‐4 function is possibly involved in the genesis of allergic disease states. The search for important amino acid residues in human IL‐4 by mutational analysis of charged invariant amino acid positions identified two distinct functional sites in the 4‐helix‐bundle protein. Site 1 was marked by amino acid substitutions of the glutamic acid at position 9 in helix A and arginine at position 88 in helix C. Exchanges at both positions led to IL‐4 variants deficient in binding to the extracellular domain of the IL‐4 receptor (IL‐4R(ex)). In parallel, up to 1000‐fold increased concentrations of this type of variant were required to induce T‐cell proliferation and B‐cell CD23 expression. Site 2 was marked by amino acid exchanges in helix D at positions 121, 124 and 125 (arginine, tyrosine and serine respectively in the wild‐type). IL‐4 variants affected at site 2 exhibited partial agonist activity during T‐cell proliferation; however, they still bound with high affinity to IL‐4R(ex). [The generation of an IL‐4 antagonist by replacing tyrosine 124 with aspartic acid has been described before by Kruse et al. (1992) (EMBO J., 11, 3237‐3244)]. These findings indicate that IL‐4 functions by binding IL‐4R(ex) via site 1 which is constituted by residues on helices A and C.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

mentioning

confidence: 99%

Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation.

et al. 1993

View full text Add to dashboard Cite

show abstract

“…An alternative splice deletion of exon 8 was also identified that results in a putative membrane-bound form of receptor lacking the intracellular signaling domain sequences. These alternative splice forms may all be involved in serving as IL9 antagonists, as is the case of other cytokine receptors (such as IL4 and IL5 receptors), although the binding affinity of these receptors is greatly reduced (37)(38)(39). 6 In addition to the splice variants described above, the abundant ⌬Q transcript was also identified.…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of Human Interleukin-9 Receptor Transcripts in Peripheral Blood Mononuclear Cells

Grasso¹,

Huang²,

Sullivan³

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Genetic studies on mouse models of asthma have identified interleukin-9 (IL9) as a determining factor in controlling bronchial hyperresponsiveness, a hallmark of the disease. Recently, the human IL9 receptor (hIL9R) gene locus has also been implicated in determining susceptibility to bronchial hyperresponsiveness and asthma. In order to evaluate the structure and function of the encoded product, we analyzed receptor transcripts derived from peripheral blood mononuclear cells of 50 unrelated donors. Sequence analysis of the entire coding region identified a splice variant that contains an in frame deletion of a single residue at codon 173 (⌬Q). This variant could be permanently expressed in a cytokine-dependent murine T-cell line but lacked the ability to induce proliferation in response to human IL9. In situ analyses of cells expressing the wild-type and ⌬Q receptors found both forms to be expressed at the cell surface, but the ⌬Q receptor was unable to bind hIL9 and could not be recognized by N-terminal specific antibodies. These findings demonstrate that hIL9R⌬Q presents an altered structure and function and suggests its potential role in down-regulating IL9 signaling in effector cells and associated biological processes.Asthma is a complex inflammatory disorder that is characterized by periodic airway obstruction, wheezing, and bronchial hyperresponsiveness (BHR) 1 (1). Clinical studies of asthma have revealed that the pathology of this disease is associated with widespread narrowing of the airways due to edema and infiltration of multiple inflammatory cells into the lung epithelia (2). These cell types include mast cells, eosinophils, B-cells, and TH2-lymphocytes as the predominant cell mediators of this disorder (3, 4). While these inflammatory cells appear to be important, their precise role in producing BHR is unclear and still under investigation. Nevertheless, the response to antigen and subsequent release of chemical inflammatory mediators (histamines, leukotrienes, prostaglandins, etc.) by a number of these cells has been documented (5).Genetic studies have suggested that BHR is a multigenic process (6 -11). Recently, we have identified interleukin-9 (IL9) as a factor in regulating airway hyperresponsivess in inbred strains of mice (12). C57BL/6 mice, which show low airway responsiveness, had undetectable levels of IL9 in activated splenocytes and in the lung, while DBA/2 mice, which have airway hypperresponsiveness, expressed robust levels of IL9 in both tissues. A role for IL9 in asthma and allergy has been supported by the findings that it has pleiotropic activities on cell types associated with these diseases such as TH2 lymphocytes, B-cells, mast cells, and eosinophils (13-19). In particular, IL9 has been shown to act as a growth and differentiation factor for mast cells and to enhance the release of IgE from B-cells. These two activities as well as the effect of IL9 on controlling BHR in mice suggest that it and its associated pathway(s) are involved in the pathogenesis of allergy and asthma. Mo...

show abstract

“…Recombinant sIL–4R was shown to neutralize IL–4 in vitro [8, 9]and in vivo [10, 11]suggesting that sIL–4R is a potential antagonist to IL–4, IL–4–driven proliferation and IL–5 upregulation by CD45RA+ human T cells were completely inhibited by human, but not murine recombinant sIL–4R. Therefore, sIL–4R seems to be a candidate to inhibit IL–4 bioactivity in vivo in diseases associated with IL–4 overproduction.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, in mice two different cDNAs originating from the same gene were observed, one coding for the cell surface and the other for the sIL–4R [7]. Recombinant forms of the sIL–4R neutralize IL–4 in vitro [8, 9]and in vivo [10, 11]suggesting that sIL–4R is an antagonist to IL–4. However, IL–4 complexed to murine sIL–4R was found to be protected from proteases resulting in a prolonged half–life [12], a fast dissociation rate [12]and enhanced IgE synthesis in vivo [13].…”

Section: Introductionmentioning

confidence: 99%

Soluble Human Interleukin–4 Receptor Is Produced by Activated T Cells under the Control of Metalloproteinases

Jung¹,

Schrader²,

Hellwig³

et al. 1999

Int Arch Allergy Immunol

View full text Add to dashboard Cite

Background: Soluble interleukin 4 receptors (sIL–4R) are present in biological fluids. In contrast to mice, in man no distinct mRNA coding for sIL–4R has been described, suggesting that human sIL–4R is exclusively produced by proteolytic cleavage of the cell surface receptor. It is not known whether human sIL–4R is actively produced during an immune response. Methods: Human purified T cells, CD4+, CD8+, CD45RA+ and CD45R0+ T cell subpopulations were activated in vitro. sIL–4R was determined in the supernatants, cell surface IL–4R was measured by flow cytometry and RT–PCR. Results: Recombinant sIL–4R inhibited IL–4–mediated proliferation and IL–5 upregulation by T cells. sIL–4R could be detected at low levels in supernatants of nonactivated T cells, but at high levels following TCR engagement. This response was paralleled by enhanced transcription and de novo synthesis of the human cell surface IL–4R. Both, activated naive CD45RA+ and memory CD45R0+ T cells, produced sIL–4R with long–lasting kinetics. IL–4 increased sIL–4R production by activated CD45RA+, but there was less of an increase by CD45R0+ T cells. In addition, interferon–γ enhanced sIL–4R production. Cycloheximide and dexamethasone inhibited sIL–4R production by activated T cells, but did not abolish constitutive release of sIL–4R. Phosphoramidon and 1,10–phenanthroline dose–dependently inhibited shedding of the IL–4R, even in nonactivated T cells. Conclusion: The production of human sIL–4R by T cells is regulated by TCR stimuli, IL–4 and IFN–γ and needs the activity of metalloproteinases. Thus, sIL–4R should be regarded as inducible and due to its IL–4–antagonizing activity an immunoregulatory molecule.

show abstract

A recombinant extracellular domain of the human interleukin 4 receptor inhibits the biological effects of interleukin 4 on T and B lymphocytes

Cited by 59 publications

References 34 publications

Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation.

Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation.

Molecular Analysis of Human Interleukin-9 Receptor Transcripts in Peripheral Blood Mononuclear Cells

Soluble Human Interleukin–4 Receptor Is Produced by Activated T Cells under the Control of Metalloproteinases

Contact Info

Product

Resources

About