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Molecular mechanisms of soluble cytokine receptor generation.

ABSTRACT: Soluble cytokine receptors play key roles in regulating cytokine-mediated biological events by binding and modulating the activity of target ligands in either an antagonistic or agonistic fashion. This Minireview will provide an overview of the molecular mechanisms mediating the generation of soluble cytokine receptors, which include sheddase-mediated proteolytic cleavage of cell-surface receptors, generation of soluble receptors by alternative gene splicing, transcription and translation of cytokine-binding genes, and extracellular release of membrane-bound receptors within vesicles such as exosomes.

SUBMITTER: Levine SJ

PROVIDER: S-EPMC2386928 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Molecular mechanisms of soluble cytokine receptor generation.

Levine Stewart J SJ

The Journal of biological chemistry 20080401 21

Soluble cytokine receptors play key roles in regulating cytokine-mediated biological events by binding and modulating the activity of target ligands in either an antagonistic or agonistic fashion. This Minireview will provide an overview of the molecular mechanisms mediating the generation of soluble cytokine receptors, which include sheddase-mediated proteolytic cleavage of cell-surface receptors, generation of soluble receptors by alternative gene splicing, transcription and translation of cyt ...[more]

PMID: 18385130

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Project description:UnlabelledThe inability to match rheumatoid arthritis (RA) patients with the anti-cytokine agent most efficacious for them is a major hindrance to patients’ speedy recovery and to the clinical use of anti-cytokine therapy. Identifying predictive biomarkers that can assist in matching RA patients with more suitable anti-cytokine treatment was our aim in this report. The sample consisted of 138 RA patients (naïve and non-naïve) who were administered tocilizumab or etanercept for a minimum of 16 weeks as a prescribed RA treatment. Pretreatment serum samples were obtained from patients and clinical measures of their disease activity were evaluated at baseline and 16 weeks after treatment commenced. Using patients’ pretreatment serum, we measured 31 cytokines/chemokines/soluble receptors and used multiple linear regression analysis to identify biomarkers that correlated with patients’ symptom levels (DAS28-CRP score) at week 16 and multiple logistic analyses for biomarkers that correlated with patients’ final outcome. The results revealed that sgp130, logIL-6, logIL-8, logEotaxin, logIP-10, logVEGF, logsTNFR-I and logsTNFR-II pretreatment serum levels were predictive of the week 16 DAS28-CRP score in naïve tocilizumab patients while sgp130, logGM-CSF and logIP-10 were predictive in non-naïve patients. Additionally, we found logIL-9, logVEGF and logTNF-α to be less reliable at predicting the week 16 DAS28-CRP score in naïve etanercept patients. Multiple linear regression and multiple logistic regression analyses identified biomarkers that were predictive of remission/non-remission in tocilizumab and etanercept therapy. Although less reliable than those for tocilizumab, we identified a few possible biomarkers for etanercept therapy. The biomarkers for these two therapies differ suggesting that their efficacy will vary for individual patients. We discovered biomarkers in RA pretreatment serum that predicted their week 16 DAS28-CRP score and clinical outcome to tocilizumab therapy. Most of these biomarkers, especially sgp130, are involved in RA pathogenesis and IL-6 signal transduction, which further suggests that they are highly reliable.Trial registrationUMIN-CTR Clinical Trial UMIN000016298.

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Molecular mechanisms of soluble cytokine receptor generation.

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Molecular mechanisms of soluble cytokine receptor generation.

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