Interaction of indomethacin with cytokine production in whole blood. Potential mechanism for a brain-protective effect

Bour, A.; Westendorp, Rudi G.J.; Laterveer, J.C.; Bollen, E.; Remarque, Edmond J.

doi:10.1016/s0531-5565(00)00128-5

Cited by 37 publications

(26 citation statements)

References 25 publications

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“…Conversely, PGE2 inhibition by indomethacin partly inhibited IL-6 secretion by MSCs. This feedback regulatory loop has already been reported in other model systems [35]. The key role of PGE2 in MSC-mediated immunosuppression is supported by results from a recent study showing that PGE2 represents the key inhibitory mediator of DC differentiation and maturation and as a consequence, of reduced T cell activation [36].…”

Section: Discussionsupporting

confidence: 66%

IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

et al. 2010

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BackgroundBased on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSC) are intensively studied for various clinical applications. Although it has been shown in vitro that the immunomodulatory effect of MSCs mainly occurs through the secretion of soluble mediators, the mechanism is still not completely understood. The aim of the present study was to better understand the mechanisms underlying the suppressive effect of MSCs in vivo, using cells isolated from mice deficient in the production of inducible nitric oxide synthase (iNOS) or interleukin (IL)-6 in the murine model of collagen-induced arthritis.Principal FindingsIn the present study, we show that primary murine MSCs from various strains of mice or isolated from mice deficient for iNOS or IL-6 exhibit different immunosuppressive potential. The immunomodulatory function of MSCs was mainly attributed to IL-6-dependent secretion of prostaglandin E2 (PGE2) with a minor role for NO. To address the role of these molecules in vivo, we used the collagen-induced arthritis as an experimental model of immune-mediated disorder. MSCs effectively inhibited collagen-induced inflammation during a narrow therapeutic window. In contrast to wild type MSCs, IL-6-deficient MSCs and to a lesser extent iNOS-deficient MSCs were not able to reduce the clinical signs of arthritis. Finally, we show that, independently of NO or IL-6 secretion or Treg cell induction, MSCs modulate the host response by inducing a switch to a Th2 immune response.SignificanceOur data indicate that MSCs mediate their immunosuppressive effect via two modes of action: locally, they reduce inflammation through the secretion of anti-proliferative mediators, such as NO and mainly PGE2, and systemically they switch the host response from a Th1/Th17 towards a Th2 immune profile.

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Section: Discussionsupporting

confidence: 66%

IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

et al. 2010

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“…IL-6 was also an important mediator because its production by MSC and fibroblasts was induced in proliferative assays. IL-6 production is induced by PGE2 and NO, as shown by the inhibitory effects of indomethacin and l-NAME, as already reported 18 19. IL-6 was also reported to regulate the production of PGE2 and NO indicating a feedback loop 20 21.…”

Section: Discussionsupporting

confidence: 58%

Skin fibroblasts are potent suppressors of inflammation in experimental arthritis

Bouffi

Bony

Jørgensen

et al. 2011

Annals of the Rheumatic Diseases

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“…The pro-inflammatory responsiveness of these patients was evaluated by measuring the levels of IL-6, IL-1β and TNF-α in whole-blood samples after stimulation with LPS [27,28]. Aliquots (3 ml) of the whole-blood samples were incubated for 24 h under sterile conditions at 37 • C with saline or LPS (Sigma) at a dose of 100 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

Association between serum values of C-reactive protein and cytokine production in whole blood of patients with Type 2 diabetes

et al. 2007

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Diabetes mellitus accelerates atherosclerotic processes, and it is known that inflammation plays a key role in atherosclerosis. The aim of the present study was to evaluate in patients with Type 2 diabetes whether serum levels of CRP (C-reactive protein) are associated with cytokine production in whole blood. A total of 89 outpatients with Type 2 diabetes were enrolled, and blood pressure, body mass index, fasting blood glucose, glycated haemoglobin, cholesterol, triacylglycerols (triglycerides) and hs-CRP (high-sensitivity CRP) were measured. IL-6 (interleukin-6), IL-1beta (interleukin-1beta) and TNF-alpha (tumour necrosis factor-alpha) were measured before and after 24 h of incubation of whole blood with LPS (lipopolysaccharide) or saline. The basal values of IL-1beta, IL-6 and TNF-alpha were low and were not significantly related to hs-CRP levels. A univariate analysis showed that the level of IL-1beta and IL-6, obtained after 24 h of incubation of whole blood with LPS, increased significantly with increasing levels of hs-CRP and, after adjusting for potential confounders, IL-1beta still remained statistically significant. In our sample of patients with Type 2 diabetes, there was no association between serum hs-CRP levels and basal levels of IL-6, IL-1beta and TNF-alpha. Conversely, a significant association was observed between serum hs-CRP levels and IL-1beta and IL-6 production after 24 h of incubation of whole blood with LPS. In conclusion, our data suggest that patients with Type 2 diabetes and high hs-CRP levels may have an enhanced reactivity in response to specific stimuli that produce different interleukins, with possible implications in inflammatory atherosclerotic processes.

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Interaction of indomethacin with cytokine production in whole blood. Potential mechanism for a brain-protective effect

Cited by 37 publications

References 25 publications

IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

Skin fibroblasts are potent suppressors of inflammation in experimental arthritis

Association between serum values of C-reactive protein and cytokine production in whole blood of patients with Type 2 diabetes

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