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Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107
Cytokine-mediated enhancement of spontaneous cytotoxicity depends,
at least in part, on modulation of the expression of surface molecules
responsible for recognition of target cell structures and triggering or
inhibition of the cytotoxic machinery. We previously demonstrated that
expression of transcription factors (e.g., Egr-1, JunB, and c-Fos) is
differentially regulated by IL-2 and IL-12. Here we show that
expression of CD161/NKR-P1A, a molecule involved in triggering
cytotoxicity, is specifically up-regulated by IL-12.
CD161 transcription, mRNA accumulation, and
surface expression are increased by IL-12. Other cytokines sharing the
IL-2R ß- and/or common 
-chains (i.e., IL-15, IL-4, and IL-7) do
not mediate these effects. In an effort to analyze the mechanisms by
which IL-2, IL-12, and IL-15 differentially regulate gene
transcription, we have isolated a novel gene,
197/15a, the expression of which in NK
and T cells is down-regulated by IL-2 and IL-15, up-regulated by IL-12,
and not affected by IL-4 and IL-7. IL-2 and IL-15 act, at least in
part, repressing 197/15a transcription;
their effect on 197/15a mRNA accumulation
is partially independent of novel protein synthesis, likely not
mediated by JunB, Bcl-2, or Bax, and requires the activity of
rapamycin-sensitive molecule(s). The observation that IL-2 and IL-12
differentially modulate CD161 expression suggests the
existence of cytokine-specific mechanisms of modulation of spontaneous
cytotoxicity based on the regulation of expression of surface molecules
involved in target cell recognition and/or triggering of the cytolytic
machinery.
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