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B Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-
During T Cell Activation1 ,2
Departments of
*
Immunology and
Tissue Biology, Jerome H. Holland Laboratory, American Red Cross, Rockville, MD 20855
Members of TNF superfamily are characterized by their
ability to inflict apoptosis upon binding to their cognate receptors in
a homotrimeric manner. These proteins are expressed on different cell
types under various conditions. However, the mechanisms governing the
expression of these molecules remain elusive. We have found that the
TCR signal can elicit the expression of receptor activator of NF-
B
ligand (RANKL), TNF-
, CD95L, and TNF-related apoptosis inducing
ligand (TRAIL) in T cell hybridoma A1.1 cells, thus allowing us to
examine the expression pattern of these molecules under precisely the
same conditions. We have previously reported that CD95L expression
requires both protein kinase C (PKC) translocation and Ca2+
mobilization and is inhibited by cyclosporin A, and dexamethasone. We
demonstrate now that activation-induced expression of RANKL is mediated
by Ca2+ mobilization. PKC activation does not induce RANKL
expression nor does it synergize with the Ca2+ signal.
Activation-induced RANKL expression is blocked by cyclosporin A, but
not by dexamethasone. The expression of TNF, in contrast, is mediated
by PKC, but not by Ca2+. TNF- expression is not
inhibited by cyclosporin A, but is sensitive to dexamethasone. A1.1
cells constitutively express TRAIL at low levels. Stimulation with
anti-CD3 leads to an initial reduction and subsequent increase in
TRAIL expression. TRAIL induction is not inhibited by cyclosporin A,
but highly sensitive to dexamethasone. Therefore, expression of the TNF
superfamily genes is regulated by distinct signals. Detailed
understanding of the regulatory mechanisms could provide crucial
information concerning the role of these molecules in the modulation of
the immune system.
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