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In vivo modulation of soluble "antagonistic" IL-6 receptor synthesis and release in ESRD
Bruno Memoli1, Giuseppe Grandaliano, Michela Soccio
1Department of Nephrology, University Federico II of Naples, Via Tasso 91/B, Napoli 80127, Italy. memoli@unina.it
Abstract:
Soluble gp130 (sgp130) is a soluble circulating receptor of IL-6 with "antagonistic" biologic activity. It is generated independently by either shedding of the extracellular domain of membrane gp130 or alternative mRNA splicing. This study was addressed to clarify the mechanisms underlying sgp130 synthesis and release in patients who undergo regular dialysis treatment (RDT) using dialytic membranes with different biocompatibility. Two groups of RDT patients were enrolled: 11 patients who were treated with cellulosic membranes (C) and 10 patients who were treated with synthetic membranes (S). Ten healthy subjects constituted the control group. Serum samples and peripheral blood mononuclear cells (PBMC) were harvested in all groups (before dialysis in RDT patients). PBMC were cultured for 24 h in the absence or presence of LPS. The serum levels of sgp130 were significantly higher in C group than in control and S patients (C, 603.1 +/- 89.9; control, 396 +/- 49.5; S, 423.4 +/- 27.7 ng/ml; P < 0.01). PBMC from C patients, in the absence of any mitogenic stimulation, released a significantly greater amount of sgp130 as compared with S and control groups (C, 532.6 +/- 161.2; S, 332.4 +/- 148.6; control, 341.4 +/- 125.4 pg/ml; P < 0.01). The sgp130 release was positively correlated with the release of both IL-6 (r = 0.336, P < 0.05) and sIL-6R receptor (r = 0.324, P < 0.05). A significantly higher gp130 gene expression was also observed in unstimulated PBMC from C patients when compared with control and S groups. It is interesting that the expression of the 85-bp exon characteristic of the alternative splicing mRNA for sgp130 was low in all groups. Finally, confocal microscopy analysis showed an increased expression of gp130 on cell surface in unstimulated PBMC from C patients as compared with control and S groups. Our results demonstrate that in patients on RDT with C membranes, the synthesis and release of sgp130 "antagonistic" receptor is significantly increased. This release is seemingly due to a shedding of membrane-bound gp130 receptor. The increased sgp130 release may partially counteract the inflammatory effects caused by IL-6.
Insights
Soluble gp130 (sgp130) levels are elevated in patients undergoing regular dialysis treatment (RDT) with cellulosic membranes. This increase, primarily due to receptor shedding, may help mitigate IL-6-driven inflammation.
Area of Science:
- Immunology
- Nephrology
- Biochemistry
Background:
- Soluble gp130 (sgp130) is a circulating antagonist of Interleukin-6 (IL-6).
- sgp130 is produced via membrane shedding or alternative mRNA splicing.
- Understanding sgp130 regulation is crucial in conditions involving IL-6 signaling.
Purpose of the Study:
- To investigate the mechanisms of sgp130 synthesis and release in patients undergoing regular dialysis treatment (RDT).
- To compare sgp130 production using different dialytic membrane biocompatibilities (cellulosic vs. synthetic).
- To elucidate the relationship between sgp130, IL-6, and IL-6 receptor (sIL-6R) in RDT patients.
Main Methods:
- Serum and peripheral blood mononuclear cells (PBMC) were collected from RDT patients (cellulosic and synthetic membranes) and healthy controls.
- PBMC were cultured with or without lipopolysaccharide (LPS) stimulation.
- sgp130 and IL-6 levels were measured in serum and PBMC culture supernatants; gp130 gene expression and cell surface expression were also assessed.
Main Results:
- Serum sgp130 levels were significantly higher in patients using cellulosic membranes compared to synthetic membranes and controls.
- Unstimulated PBMC from patients on cellulosic membranes released significantly more sgp130, correlating positively with IL-6 and sIL-6R release.
- Increased gp130 gene and cell surface expression were observed in PBMC from patients on cellulosic membranes, suggesting shedding as the primary sgp130 source.
Conclusions:
- Regular dialysis treatment with cellulosic membranes significantly increases sgp130 synthesis and release in RDT patients.
- The elevated sgp130 release appears to be mainly due to shedding of membrane-bound gp130.
- Increased sgp130 may serve as a compensatory mechanism to counteract IL-6-mediated inflammatory effects during RDT.
