Serum levels of apoptosis molecules trail and receptors dr-4 and dr-5 and their relation with fas/fas ligand system in patients with non-hodgkin?s lymphoma: evaluation of their role in the pathogenesis and prognosis.

Diffuse large B-cell lymphoma (DLBCL) is the most common type (30%) and aggressive form of lymphoma. Lymphocyte proliferation and stability in germinal center take place through apoptosis. Two distinct apoptotic pathways, extracellular and intracellular, work together. The extracellular pathway often is controlled by TRAIL receptors and Fas/Fas-L TNF family members. As a result of the ligand and receptor interaction, intracellular death domain becomes active and finally leads to caspase activation and apoptosis. In this study, we aimed to clarify the role of receptors and ligands important in the pathogenesis of DLBCL and their relationship with the clinical data. TRAIL, TRAIL-DR4 and TRAIL-DR5 levels together with the Fas/Fas-L levels were determined, and their significance in comparison with the clinical parameters is assessed before and after the treatment in patients with DLBCL. Forty-seven (25 females and 22 males) patients diagnosed as having DLBCL between January 2005 and October 2007 were prospectively enrolled in the study. A control group consisting of 32 healthy subjects (20 females and 12 males) was included in the study. The patients? sera were collected before and after the treatment. Serum levels of soluble TRAIL, TRAIL-DR4, TRAIL-DR5, Fas and Fas-L were determined with ELISA method. Soluble TRAIL, TRAIL-DR4, TRAIL-DR5, Fas and Fas-L levels were higher in the patient group compared to the controls (p<0,001). TRAIL-DR5 and Fas levels were correlated with the clinical IPI scores and LDH levels. On the other hand, TRAIL-DR5 was in stage III-IV patients compared to stage I-II patients (p<0,05). Pre and post treatment Fas levels found to be statistically significant (5,39±4,5 ng/ml and 6,33± 4,58 ng/ml, respectively) (p<0,05). DR5 levels positively correlated with DR4 and Fas 46 levels, whereas correlated negatively with soluble TRAIL levels. The IPI scores correlated with LDH, B symptoms and disease stage (p<0,05). Higher IPI scores predicted worse OS (p<0,05). A positive correlation was seen between patients with elevated LDH, extranodal disease and B symptoms (p<0,05). More patients with B symptoms had extranodal disease (p<0,05). Soluble human TRAIL itself is used in the treatment of lymphoma. Studies using Fas in the treatment of these patients are no longer being done because of excessive toxicity. In our study, we showed that these receptors and ligands play an important role in pathogenesis of DLBCL. Clinical and translational studies are warranted to help better understand these signaling pathways in an attempt to intervene using agents targeting these pathways.