Soluble Fas antigen can protect cells against Fas-mediated apoptosis. High level soluble Fas antigen characteristic for blood of patients with autoimmune disease or cancer is believed to prevent the elimination of autoimmune lymphocytes or tumor cells. Here we first report that human recombinant Fas⌬TM, i.e. soluble Fas generated by alternative splicing of the intact exon 6, is capable of inducing death of transformed cells by "reverse" apoptotic signaling via transmembrane Fas ligand. Fas⌬TM, as well as transmembrane Fas antigen, can be either monomeric or oligomeric, and both its forms are efficient in blocking Fas-mediated apoptosis, although the cytotoxic activity is exhibited solely by the latter. An in vivo analysis of soluble Fas antigen showed that unlike in healthy controls, nearly the total Fas⌬TM present in sera of rheumatoid arthritis patients was oligomeric. This resulted in suppression of cell proliferation in the experimental sera and in its promotion in controls. Thus, oligomerization/depolymerization of soluble Fas antigen can regulate its activity and contribute to the pathogenesis of autoimmune diseases and cancer.Receptors and their ligands from the families of TNF 1 receptors and TNF ligands are crucial for cell proliferation, differentiation, and death. Some of these functions are realized through ligand-induced activation of transmembrane receptors with subsequent signal transduction to the receptor-expressing cell. The molecular mechanisms of this kind of transduction are well studied and described in many reviews (1-3). Other functions performed by the TNF receptor-ligand system are realized through the so-called "reverse signaling", with transmembrane ligand acting as a receptor, i.e. a molecule that receives and delivers the signal, and the receptor (soluble or transmembrane) serving as a ligand, i.e. the signaling molecule. The reverse signaling has been shown for many members of the TNF ligand family (4 -11). However, the activation modes and pathways of the reverse signal are virtually unexplored and rarely reported on (11-17).Fas antigen (Fas) and Fas ligand (FasL) play a key role in maintaining homeostasis of the immune system. FasL-induced activation of transmembrane Fas resulting in death of Fasbearing cells underlies selection of T-and B-lymphocytes and target elimination by T-and natural killers (3, 18). FasLmediated reverse signaling was first revealed independently by two research teams (9, 10) and shown to participate in growth control of CD8ϩ and CD4ϩ T-lymphocytes. Suzuki and Fink (9,19,20) reported that cross-linked FasIgG enhanced proliferation of CD8ϩ T-lymphocytes. Desbarats et al. (10) showed that activation of transmembrane Fas ligand on CD4ϩ T-lymphocytes inhibited expression of IL-2, thereby suppressing cell proliferation and causing cell death. Presumably, signal transduction via Fas ligand involves kinases Erk 1 and 2, phospholipase A2, and some proteins containing SH3 and WW domains, specifically, Fyn kinase (14 -16).The current study deals with the possibilit...

No abstract

No abstract