Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients

Abstract

Dysregulation of apoptosis, particularly in the Fas/Fas ligand (FasL) pathway, is considered to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Recently, a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds FasL and inhibits FasL-induced apoptosis, has been identified. Silicosis is clinically characterized not only by respiratory disorders but by immunological abnormalities. We have found that serum soluble Fas (sFas) levels are elevated in silicosis patients and that sFas message is dominantly expressed in PBMC derived from these patients. This study examined DcR3 gene expression in PBMC derived from patients with silicosis, SLE, or progressive systemic sclerosis (PSS), and compared it with that in healthy volunteers (HV). The relative expression level of the DcR3 gene was examined in PBMC derived from 37 patients with silicosis without clinical symptoms of autoimmune disease, nine patients with SLE, 12 patients with PSS, and 28 HV using the semiquantitative multiplex-reverse transcriptase-polymerase chain reaction (MP-RT-PCR). The correlation between the relative expression level of the DcR3 gene and multiple clinical parameters for respiratory disorders and immunological abnormalities in individuals with silicosis was analysed. The DcR3 gene was significantly over-expressed in cases of silicosis or SLE when compared with HV. In addition, the DcR3 relative expression level was positively correlated with the serum sFas level in silicosis patients. It is unclear, however, whether over-expression of the DcR3 gene in silicosis is caused by chronic silica exposure, merely accompanies the alteration in Fas-related molecules, or precedes the clinical onset of autoimmune abnormalities. It will be necessary to study these patients further, establish an in vitro model of human T cells exposed recurrently to silica compounds, and resolve whether the increase in DcR3 mRNA expression is a cause or consequence of disease.

The Glycosaminoglycan-Binding Domain of Decoy Receptor 3 Is Essential for Induction of Monocyte Adhesion

“…DcR3 is overexpressed in malignant tumors arising from lung, colon, glioma, and gastrointestinal track; virus-associated lymphoma (1, 4 -7); as well as the PBMC of silicosis patients (8). In addition, high serum levels of DcR3 have been detected in many cancer patients (9) and are associated with poor prognoses (6).…”

Detection of anti-topoisomerase I autoantibody in patients with silicosis

“…We found that dysregulation of the Fas-mediated apoptotic pathway might play an important role in the pathogenesis of the immunological abnormalities found in silicosis patients 7,8,[17][18][19] . Therefore, it is suggested that the genesis of anti-topo I autoantibodies is associated with the abnormalities of apoptosis-related molecules in silicosis patients.…”

“…In addition, silicosis patients in the anti-topo I (+) group showed inverse correlations between the serum sFas levels and PaCO 2 values, although patients in the anti-topo I (−) group did not. Moreover, our previous studies 7,19) on dysregulation of the Fas/FasL pathway showed that the same series of patients with silicosis or SLE showed higher serum sFas levels and over-expres- sion of the decoy receptor 3 gene in peripheral blood mononuclear cells, while SSc patients did not. These findings suggest that the genesis of anti-topo I autoantibodies is related to pulmonary involvement or lung fibrosis associated with progression of silicosis, and that it may have little association with dysregulation of the Fas-mediated apoptotic pathway.…”

Immunological Effects of Silica and Related Dysregulation of Autoimmunity

“…The weaker membrane Fas expressers (among lymphocytes) were identified to be weaker fas message expressers . The gene expression levels of extracellular inhibitor competing membrane Fas-FasL binding such as sFas, decoy receptor 3 (DCR3), and other alternatively spliced variants of the fas gene were higher in peripheral blood mononuclear cells (PBMC) from SILs than HVs (Otsuki, 2000a(Otsuki, , 2000b. The intracellular apoptosis-inhibitory genes including i-flice, sentrin, survivine and icad showed a lower expression in PBMC from SILs than HDs (Guo, 2001;Otsuki, 2000c).…”