A soluble form of the murine common gamma chain is present at high concentrations in vivo and suppresses cytokine signaling.
The common gamma-chain (gammac) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble gammac (sgammac) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the full-length gammac showed that shedding of the transmembrane receptor led to the release of sgammac. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence sgammac release. In vivo, superantigen-induced stimulation of T cells enhanced sgammac serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of sgammac. A physiological role of sgammac was indicated by its capacity to specifically inhibit cell growth induced by gammac-dependent cytokines. Mutational analysis revealed that the C-terminus and the WSKWS motif are essential for the cytokine inhibitory effect of the sgammac and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane gammac by excess sgammac is the most likely mechanism of cell growth inhibition. It was implied that naturally produced sgammac is a negative modulator of gammac-dependent cytokines.
Meissner
U
U
Institute for Clinical Microbiology, Immunology and Hygiene, University of Erlangen-Nuremberg, Erlangen, Germany.
Blum
H
H
Schnare
M
M
Röllinghoff
M
M
Gessner
A
A
D020816:Amino Acid Motifs; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects* / Q000494:pharmacology / Q000502:physiology*; D003864:Depression, Chemical; D005260:Female; D053631:Interleukin Receptor Common gamma Subunit; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases; D051379:Mice; D008815:Mice, Inbred Strains / Q000378:metabolism; D008817:Mice, Mutant Strains / Q000378:metabolism; D016513:Mice, SCID / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D018123:Receptors, Interleukin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D014407:Tumor Cells, Cultured
D016207:Cytokines; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D021122:Protein Subunits; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D010447:Peptide Hydrolases; D008666:Metalloendopeptidases