Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Adrenomedullin Induces Semi-Matured Tolerogenic Dendritic Cells: Implication of a Neuropeptide in Peripheral Tolerance

Rulle1,  Sandrine, Ah Kioon2,  Marie-Dominique, Asensio2,  Carine, Ea2,  Hang-Korng, Boissier1,  Marie-Christophe, Liote2,  Frederic, Falgarone1,  Geraldine

Paris 13 University; AP-HP, Bobigny, France
Rheumatology Department; Inserm UMR-S606; Paris-Diderot University, hôpital Lariboisiere, Paris, France

Purpose:

Dendritic cells (DC) are antigen presenting cells and are also important for tolerance. They can stimulate or expand regulatory T cells (Treg) to favor the immune response control. Among molecules expressed by tolerogenic DC, indoleamine dioxygenase (IDO) can promote Treg development and suppress T cell activation (1). Adrenomedullin (AM) is a neuropeptide with anti-apoptotic and anti-inflammatory effects and can reduce arthritis in collagen-induced arthritis. AM could decrease TH1 effector cells and favor Treg expansion (2). AM and its receptors are expressed by several immune cells but its role in immune homeostasis is unknown. The aim of this study is to evaluate AM effects on DC maturation and functions.

Methods:

Bone marrow-derived DC were cultured in Gm-CSF during 6 days, stimulated or not with CpG motifs, lipopolysaccharide (LPS), AM alone or in combination during 24 hours. DC maturation was evaluated by flow cytometry, cytokine titration, allogeneic T cell proliferation and endocytosis analysis. The expression of IDO, AM, AM receptors CLR/RAMP (Calcitonin receptor Like Receptor/Receptor Activating Modifying Protein) and orphan receptors RDC-1 and L1 were studied by q-RT-PCR and western blot.

Results:

In comparison with LPS- or CpG-stimulated DC, AM-stimulated DC expressed lower MHC class II, CD40, CD80 and CD86 molecules, and secreted less pro-inflammatory cytokines (IL-12p70, IL-1a, IL-1b) than mature DC; surprisingly, AM seemed to reduce LPS induced-TNF secretion and induces high levels of IFN gamma but not of IL-10.

However, allogeneic and endocytosis capacities were comparable to that of semi-mature and mature DC. Moreover, although DC expressed at basal level the AM receptor CLR, the co-factor RAMP-2, and RDC-1, DC maturation was accompanied with an increase of all these molecules. DC expressed also low level of secreted AM and exogenous AM increases this level. Finally IDO mRNA was expressed after AM stimulation.

Conclusion:

For the first time, we have demonstrated that AM and its receptors are expressed in DC and that exogenous AM is able to modify DC phenotype and functions. AM-stimulated DC are characterized by a semi-mature phenotype with reduced endocytic capacities. This action seems to be specific of its receptors CLR and RAMP. Through IDO expression and others yet unknown mechanisms, this effect could be involve in peripheral tolerance and could be a promising strategy to favor Treg expansion.

This work was funded by the SFR (French Society of Rheumatology) and the Arthritis Fundation-Courtin.

1.Jaen, O, et al. Dendritic cells modulated by innate immunity improve collagen-induced arthritis and induce regulatory T cells in vivo. Immunology 2009; 126:35-44.

2.Gonzalez-Rey, E, et al. Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 2007;170:263-71.

To cite this abstract, please use the following information:
Rulle, Sandrine, Ah Kioon, Marie-Dominique, Asensio, Carine, Ea, Hang-Korng, Boissier, Marie-Christophe, Liote, Frederic, et al; Adrenomedullin Induces Semi-Matured Tolerogenic Dendritic Cells: Implication of a Neuropeptide in Peripheral Tolerance [abstract]. Arthritis Rheum 2009;60 Suppl 10 :143
DOI: 10.1002/art.25226

Abstract Supplement

Meeting Menu

2009 ACR/ARHP