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Blood, 1 January 2001, Vol. 97, No. 1, pp. 183-191
IMMUNOBIOLOGY
A soluble form of the murine common  chain is present at high
concentrations in vivo and suppresses cytokine signaling
Udo Meißner,
Horst Blum,
Markus Schnare,
Martin Röllinghoff, and
André Gessner
From the Institute for Clinical Microbiology,
Immunology and Hygiene, University of Erlangen-Nuremberg, Erlangen,
Germany.
The common gamma-chain ( c) 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 c (sc) 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 c showed
that shedding of the transmembrane receptor led to the release of
sc. The shedding enzymes, however, appeared to be distinct from
those cleaving other cytokine receptors because inhibitors of
metalloproteases (eg, TAPI) did not influence sc release. In vivo,
superantigen-induced stimulation of T cells enhanced sc 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 sc. A physiological role of sc was
indicated by its capacity to specifically inhibit cell growth induced
by c-dependent cytokines. Mutational analysis revealed that the
C-terminus and the WSKWS motif are essential for the cytokine
inhibitory effect of the sc and for binding of the molecule to
cytokine receptor-expressing cells. Thus, competitive displacement of
the transmembrane c by excess sc is the most likely mechanism of
cell growth inhibition. It was implied that naturally produced sc is
a negative modulator of c-dependent cytokines.
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