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Excerpt
In end-stage heart failure (HF) elevated levels of TNF-α are reported, while high levels of soluble TNF-α receptors are present after hearttransplantation (HTX). Both observations might indicate activation of the TNF-α system. However, the activity of the TNF-α system is the resultant of mRNA transcription, free protein levels and the binding capacity of the soluble receptors. In an attempt to assess the true activity of the TNF-α system we measured its various components: mRNA expression of PBMC by quantitative RT-PCR, free plasma levels of TNF-α and its soluble receptors 1 and 2 by ELISA, and the TNF-α-binding capacity by in-vitro recovery studies. We studied 11 HF patients, 15 HTX patients and 12 healthy controls. We were not able to detect free TNF-α in plasma samples before or after hearttransplantation. TNF-α mRNA expression in patients PBMC was not significantly different from that of healthy controls(TNF-α: 21 fg (controls) vs 18 fg (HF) vs 27 fg (HTX), N.S.). However, both in HF and HTX patients significantly higher sTNF-receptor levels were found compared to controls. (controls: R1: 0.7 ± 0.1; R2: 1.6± 0.5 ng/ml. HF: R1 2.6 ± 1.7; R2: 5.6 ± 2.7 ng/ml, p<0.003 vs HTX. p<0.0001 vs controls. HTX: R1: 1.6 ± 0.5; R2: 4.4 ± 1.0 ng/ml, p<0.0001 vs controls. The recovery of rec.TNF-α after incubation with patients plasma was significantly lower compared to incubation with control plasma (75±5% vs 100±7%, p<0.05). Both soluble receptors showed a linear relation with renal function R1:r=0.89; R2:r=0.84). Serum creatinine in HF was 107 µmol/l, range 53-390, in HTX: 113 µmol/l, range 63-140. On the basis of the normal mRNA expression and TNF-α levels we conclude that the TNF-α system is not upregulated before (HF) or after hearttransplantation (HTX). In contrast the high soluble TNF-receptors levels and their elevated TNF-α binding capacity result in a decreased bioavailability of TNF-α. Both in heart failure and after hearttransplantation the TNF-α system is out of balance which contributes to the immunosuppressed state of the patients.
