Soluble human interleukin-4 receptor is produced by activated T cells under the control of metalloproteinases

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.