capases mediated pleiotropy exhibited by TRAIL

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has gained

much attention as a possible therapeutic reagent for the treatment of tumors, as

TRAIL was originally described to induce apoptosis specifically in cancer cells, but

not in normal cells. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA)

patients exhibit tumor-like features and we have described earlier that TRAIL

induces apoptosis only in a subset of RA FLS, but an induction of proliferation in

the surviving cells. This observation corresponds to the pleiotropic effects of

TRAIL observed on primary human tumor cells. Here, we describe that the PI3

kinase/Akt-signaling pathway, but not that of the MAP kinases ERK and p38, protects

RA FLS from TRAIL-induced apoptosis by modulating the expression of the cell

survival regulators p21, XIAP, Mcl-1 and RIP. Moreover, we found that not only

TRAIL-induced apoptosis, but also TRAIL-triggered proliferation in RA FLS is

mediated by caspases with a crucial role for caspase 8. TRAIL was found to induce

degradation of p21 and p27 that was caspase-dependent, but independent of the ERK,

p38 and PI3 kinase/Akt-signaling pathways. The finding that TRAIL-triggered

proliferation and apoptosis share intracellular routes has to be taken in

consideration in defining therapeutic strategies on the basis of the administration

of TRAIL.


Apoptosis: it is atype of programmed cell death

pleiotropy- action of a single gene on multiple phenotypic traits.thatis single gene product may be usedby different cells or it may have signaing function on different targets