Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome.
Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is a disorder characterized by debilitating fatigue associated with immunological abnormalities and cognitive impairments. The recently cloned RNase L Inhibitor (RLI) gene encodes a specific protein which is believed to regulate 2-5A synthetase and RNase L activity via the formation of a latent heterodimeric protein complex. In the present study, we investigated the levels of 2-5A synthetase, RNase L and RLI in patients with CFIDS as compared to healthy controls. Quantitative Competitive PCR (Q/C PCR) analysis showed a statistically significant decrease in RLI mRNA present in the peripheral blood lymphocytes (PBL) of patients with CFIDS (n = 25, mean = 569, S.E = 154) as compared to RLI mRNA level present in peripheral blood lymphocytes (PBL) of healthy controls (n = 15, mean = 2296, S.E = 506; p < 0.0001). The decrease in RLI mRNA in CFIDS individuals correlated directly with RLI and RLI: RNase L protein ratio while showing an inverse relationship to the 2-5A synthetase and RNase L activity. This RLI mRNA and protein deficiency in CFIDS patients may explain the increase in activity of RNase L found in CFIDS patients. The unidirectional decrease in RLI message and protein levels in CFIDS individuals may contribute to the destabilization of the latent RLI:RNase L heterodimeric protein complex, resulting in the excessive activation of RNase L shown in this study. The increased activation of RNase L may result in an increased cellular RNA turnover and subsequent inhibition of protein synthesis; thus resulting in general fatigue, myalgia muscle weakness and other symptomatologies shown in CFIDS patients. Furthermore, this data supports the hypothesis that the antiviral 2-5 oligoadenylate synthetase (2-5OAS) overexpression in individuals with CFIDS correlates with an increase in RNase L activity and with a decrease in RNase L inhibitor.
Vojdani
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A
Immunosciences Lab., Inc., Beverly Hills, CA 90211, USA.
Choppa
P C
PC
Lapp
C W
CW
D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood*; D018528:ATP-Binding Cassette Transporters; D000328:Adult; D000368:Aged; D018833:Chaperonins; D015536:Down-Regulation; D004722:Endoribonucleases / Q000097:blood*; D015673:Fatigue Syndrome, Chronic / Q000097:blood* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation
C501917:ABCE1 protein, human; D018528:ATP-Binding Cassette Transporters; D011506:Proteins; D012333:RNA, Messenger; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D018833:Chaperonins