• Media type: E-Article
  • Title: A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling
  • Contributor: Meißner, Udo; Blum, Horst; Schnare, Markus; Röllinghoff, Martin; Gessner, André
  • Published: American Society of Hematology, 2001
  • Published in: Blood
  • Extent: 183-191
  • Language: English
  • DOI: 10.1182/blood.v97.1.183
  • ISSN: 1528-0020; 0006-4971
  • Keywords: Cell Biology ; Hematology ; Immunology ; Biochemistry
  • Abstract: <jats:title>Abstract</jats:title><jats:p>The common gamma-chain (γc) 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 γc (sγc) 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 γc showed that shedding of the transmembrane receptor led to the release of sγc. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence sγc release. In vivo, superantigen-induced stimulation of T cells enhanced sγc 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 sγc. A physiological role of sγc was indicated by its capacity to specifically inhibit cell growth induced by γc-dependent cytokines. Mutational analysis revealed that the C-terminus and the WSKWS motif are essential for the cytokine inhibitory effect of the sγc and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane γc by excess sγc is the most likely mechanism of cell growth inhibition. It was implied that naturally produced sγc is a negative modulator of γc-dependent cytokines.</jats:p>
  • Description: <jats:title>Abstract</jats:title><jats:p>The common gamma-chain (γc) 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 γc (sγc) 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 γc showed that shedding of the transmembrane receptor led to the release of sγc. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence sγc release. In vivo, superantigen-induced stimulation of T cells enhanced sγc 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 sγc. A physiological role of sγc was indicated by its capacity to specifically inhibit cell growth induced by γc-dependent cytokines. Mutational analysis revealed that the C-terminus and the WSKWS motif are essential for the cytokine inhibitory effect of the sγc and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane γc by excess sγc is the most likely mechanism of cell growth inhibition. It was implied that naturally produced sγc is a negative modulator of γc-dependent cytokines.</jats:p>
  • Footnote:
  • Access State: Open Access