Two distinct stimulus-dependent pathways lead to production of soluble murine interleukin-4 receptor.
The IL-4R exists in two forms, either membrane bound or as a soluble (s) molecule. Since the sIL-4R binds to its ligand with high affinity, thereby acting as an immunoregulatory molecule, we were interested in the processes leading to its release. First, the release of sIL-4R in the model of murine leishmaniosis was analyzed. Infection of mice with Leishmania major resulted in up-regulation of sIL-4R production by Ag-stimulated CD4+ T cells, with a maximum around 7 days after infection. To clarify the mechanisms underlying sIL-4R release, in vitro studies were performed. After stimulation of naive lymphoid cells with IL-4, sIL-4R release was dependent on up-regulation of spliced IL-4R mRNA, as shown by inhibition with specific antisense oligonucleotides. In contrast to this, no increase in the spliced IL-4R mRNA and no inhibitory influence of antisense oligonucleotides were observed after stimulation of T cells from IL-4-deficient mice with anti-CD3 mAb. Thus, TCR stimulation can lead to IL-4-independent sIL-4R production. Under these conditions proteolytic shedding of membrane-bound IL-4R appears to be the principal mechanism of release, since in contrast to stimulation with IL-4, iodinated sIL-4R could only be immunoprecipitated after cell surface labeling and subsequent TCR stimulation. The common gamma-chain, a component of the IL-4R complex, did not appear to be involved in the pathways leading to sIL-4R expression. This analysis suggests the existence of two differentially regulated pathways of sIL-4R release, possibly having different consequences for the regulation of IL-4 bioactivity.
Blum
H
H
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nurnberg, Germany.
Wolf
M
M
Enssle
K
K
Röllinghoff
M
M
Gessner
A
A
D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015847:Interleukin-4 / Q000378:metabolism* / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000276:immunology* / Q000378:metabolism; D019948:Receptors, Interleukin-4; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D015847:Interleukin-4