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Projet

Modulation of pro-inflammatory cytokine production

Domaines Scientifiques
Maladies
Organismes
Applications
Technique
Date de Début
01
Jul 2015
Statut
En cours
Membres
1

Présentation

Modulation of the anti-inflammatory properties of interleukin-10 by adherence(Adib-Conquy et al. Intern. Immunol. 1999, 11, 689-698; Petit-Bertron et al. J. Leuk. Biol. 2003, 73, 145-154; Petit-Bertron et al. Cytokine 2005, 29, 1-12).

Interleukin-10 (IL-10) is a well-recognized anti-inflammatory cytokine. IL-10 is also an immunostimulating cytokine, acting as a growth and differentiation factor for NK cells and B-lymphocytes. The dual role of IL-10 depends on its tissue levels, the nature of the target cell, the activating signal, the timing and sequence of cytokine exposure. We demonstrated that adherence is a parameter that markedly affects the properties of IL-10 on TNF production. Pre-incubation of whole blood samples with IL-10 before isolation of mononuclear leukocytes led to cells that were primed and, in response to LPS, produced more TNF than cells maintained in the absence of IL-10. We showed that prevention of adherence of monocytes during the pre-incubation step with IL-10 was responsible for this pro-inflammatory effect (figure).

 

 Experimental models demonstrating the influence of adherence on the properties of IL-10.

 

We also showed that the pre-treatment of monocytes with IL-10 in the absence of adherence led to an enhanced TNF mRNA expression and NF-?B activation in monocytes / macrophages in the response to LPS. IL-10 is known to increase phagocytosis and we showed that this effect was significantly amplified when the pre-treatment occurred in the absence of adherence. Tyk2 and “signal transducer and activator of transcription” (STAT) 3 phosphorylation and suppressor of cytokine signaling (SOCS) 3 expression are induced by IL-10 in human monocytes. In the presence of adherence, a longer activation and/or expression of these molecules was observed than in the absence of adherence. Finally, heme oxygenase-1 (HO-1), an anti-inflammatory molecule, was induced by IL-10 in adherent monocytes, whereas its expression remained low in non-adherent cells.

We analyzed by macroarray the effect of IL-10 and adherence on the expression of 1050 genes coding for cytokines / chemokines and their receptors, integrins, cell surface markers, proteases, molecules of cell signaling, molecules involved in cell division and cell metabolism. Interestingly, IL-10 modulated differently on Teflon® and plastic the expression of 16 genes, whose products include SOCS2, SOCS3, coproporphyrinogen oxidase (an enzyme involved in heme biosynthesis), and several matrix metalloproteinases (see figure below). This was the first demonstration that IL-10 has a potent inhibitory effect on coproporphyrinogen oxidase expression (both at the mRNA and protein levels) in adherent cells. This could be one of the mechanisms by which IL-10 contributes to the anemia known to occur after injection of IL-10 in humans. These studies demonstrate that adherence has a profound modulatory effect on IL-10 properties and the signaling induced by IL-10.

The macroarray study was done in collaboration with Thierry Pedron (Molecular Microbial Pathogenesis Unit) using the DNA chips platform of the Institut Pasteur. The analysis of coproporphyrinogen oxidase was possible thanks to the collaboration with Ulrich Gross (Johann Wolfgang Goethe-Universität, Frankfurt-am-Main). The project, and Anne-France Petit-Bertron were funded by the Association Vaincre la Mucoviscidose.

Expression by monocyte-enriched peripheral blood mononuclear cells (PBMC) of genes differently modulated by IL-10 on plastic and Teflon®. (mean of three independent experiments)

 

Modulation of TNF and IL-1 production by serotonin(Cloëz-Tayarani et al. Intern. Immunol. 2003, 15, 233-240 ; Cloëz-Tayarani et al. Life Sci. 2004, 76, 429-443)

Serotonin (or 5-hydroxytryptamine, 5-HT) is a mediator of the central nervous system. In addition to its role as a neuromediator, serotonin is present in the intestine and modulates intestinal physiology. Furthermore, serotonin is released by mast cells and by activated platelets and is present at micromolar concentrations at the inflammatory site. Several 7-fold transmembrane receptors of 5-HT have been characterized. In order to afford additional insight into the in vivo significance of 5-HT in inflammation, we examined its effects on the production of TNF, IL-1alpha, IL-1beta, IL-6, IL-10 and IL-1ra in LPS-stimulated peripheral blood mononuclear cells (PBMC). 5-HT inhibited TNF production and increased IL-1beta production in PBMC. The inhibitory effect of 5-HT on TNF production was antagonized by ketanserin, a selective 5-HT2A antagonist, and mimicked by DOI, a selective 5-HT2A/2C agonist. These findings suggest that the inhibition of TNF production by 5-HT involves the participation of the 5HT2A receptor subtype in PBMC. Accordingly, we detected the presence of 5-HT2A receptors in PBMC by Western blot. Our data support a role of 5-HT in inflammation through its effect on cytokine production by PBMC. The regulatory effect of 5-HT on cytokine production was recently confirmed with isolated monocytes (22). We also showed an activation of extracellular signal-regulated kinase (ERK) within cultured lymphocytes exposed to 5-HT. This phenomenon seems to be mediated via the 5-HT1A receptor since similar results were obtained with R-(+)-8-hydroxy-DPAT, a selective agonist of 5-HT1A receptor, and 5-HT-induced ERK phosphorylation was inhibited by WAY100635, a selective antagonist of 5-HT1A receptor. These results further illustrate that the properties and function of cells of the immune system can be modulated by numerous mediators, including neuromediators.

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