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Soluble human interleukin-4 receptor is produced by activated T cells under the control of metalloproteinases
T Jung1, N Schrader, M Hellwig
1Department of Dermatology, University of Göttingen, Germany. Thomas.Jung@Pharma.Novartis.Com
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-gamma 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-gamma 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.
Insights
Human T cells actively produce soluble interleukin 4 receptors (sIL-4R) during immune responses, regulated by T cell receptor stimuli and cytokines. This inducible sIL-4R molecule antagonizes IL-4 activity, playing a key role in immune regulation.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Soluble interleukin 4 receptors (sIL-4R) are found in biological fluids.
- Human sIL-4R is thought to be produced by proteolytic cleavage of the cell surface receptor, unlike in mice.
- The active production of human sIL-4R during immune responses remains unclear.
Purpose of the Study:
- To investigate the production and regulation of soluble interleukin 4 receptors (sIL-4R) by human T cells.
- To determine if sIL-4R is actively produced during immune responses.
- To understand the role of sIL-4R as an immunoregulatory molecule.
Main Methods:
- Human T cell subpopulations (CD4+, CD8+, CD45RA+, CD45R0+) were activated in vitro.
- Soluble IL-4R (sIL-4R) levels in supernatants were measured.
- Cell surface IL-4R expression was analyzed using flow cytometry and RT-PCR.
Main Results:
- Recombinant sIL-4R inhibited IL-4-mediated T cell proliferation and IL-5 upregulation.
- Activated T cells, including naive and memory subsets, produced high levels of sIL-4R with sustained kinetics.
- T cell receptor engagement, IL-4, and interferon-gamma significantly enhanced sIL-4R production, while metalloproteinase inhibitors reduced shedding.
Conclusions:
- Human T cells actively produce inducible soluble interleukin 4 receptors (sIL-4R) in response to T cell receptor stimuli, IL-4, and IFN-gamma.
- Metalloproteinase activity is essential for the shedding of IL-4R.
- Due to its IL-4-antagonizing properties, sIL-4R functions as a significant immunoregulatory molecule.