Effect of L-carnitine on Fas-induced apoptosis and sphingomyelinase activity in human T cell lines.

Fas is a 45 kDa type-I membrane protein and belongs to the tumor necrosis factor (TNF) receptor/nerve growth factor receptor family. The Fas ligand (FasL) is a membrane-bound cytokine and a member of the TNF family. The binding of FasL or agonist anti-Fas to Fas induces apoptosis, indicating that FasL is a death factor and that Fas is its receptor. The Fas system is involved in the development of T cells, in particular activation- induced suicide of T cells or peripheral clonal deletion. A high expression of the Fas/FasL system in peripheral blood mononuclear cells from HIV- positive subjects has been reported and could be responsible for the observed relevant apoptosis of both infected and uninfected cells. It has also been noted that expression of Fas by CD4+ T cells of HIV-infected patients negatively correlated with their CD4+ T cell count. Moreover, it has been reported that Fas stimulation by crosslinking with monoclonal antibodies induced peripheral blood T cell apoptosis in HIV-infected individuals. In contrast, antibodies against other members of the TNF/NGF receptor family, such as CD27, CD30, CD40,4–IBB, p55 TNF receptor, p75 TNF receptor, and TNF receptor-related protein all failed to induce apoptosis. In addition, the Fas system may be involved in the relative abilities of Thl and Th2 cells to undergo apoptosis since Thl clones express high levels of Fas ligand, whereas its expression on Th2 is low. This differential Fas ligand expression could explain the selective Th1 depletion observed du ring HIV infection. Other investigators using an in vitro model have shown that the effect of viral Tat protein on T cell apoptosis is mediated by increased Fas ligand expression at concentrations of Tat similar to that observed in the sera of HIV infected patients. The apoptotic signal through Fas seems to involve the activation of an acidic sphingomyelinase, sphingomyelin breakdown and ceramide production. Ceramide acts as an endogenous mediator of apoptosis in several cell lines and its potential role in the pathogenesis of HIV infection has been suggested. Ceramide has indeed been reported to increase and has been shown to potently induce HIV replication in HIV-chronically infected CEM cell line and HL60 cells, V-1IIIB and OM-10.1 cells respectively.Moreover, the ceramide treatment ofHIVLTR transfected cells strongly increases reporter CAT expression, and Rb hypophosphorylation induced by ceramide might remove the E2F-imposed transcriptional inhibition of the viral genome.