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.


CONCLUSIONS
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.
Jung
T
T
Department of Dermatology, University of Göttingen, Germany. Thomas.Jung@Pharma.Novartis.Com
Schrader
N
N
Hellwig
M
M
Enssle
K H
KH
Neumann
C
C
D000818:Animals; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
D015848:Interleukin-5; D011948:Receptors, Antigen, T-Cell; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D008666:Metalloendopeptidases