Regulation of immune tolerance by anti-inflammatory neuropeptides

González‐Rey, Elena; Chorny, Alejo; Delgado, Mario

doi:10.1038/nri1984

Cited by 206 publications

(230 citation statements)

References 103 publications

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“…A novel approach to drug discovery, based on the study of the body's own natural resolution mechanisms, is currently emerging and finding acceptance in the scientific community 27,28 : MC analogues would fit into this novel category. So far, most efforts have been devoted to the development of MC 4 agonists with potential use in obesity and sexual dysfunction, and there have been a few attempts to exploit the potential use of MC compounds as anti-inflammatory drugs. One reason behind this lack of development could be identification of the MC receptor to be targeted to elicit the desired anti-inflammatory effects, with studies pointing to each of MC 1 , 29 MC 3 , 10 and, more recently, MC 5 .…”

Section: Discussionmentioning

confidence: 99%

“…The data obtained in the in vitro MC receptor functional assays revealed that AP214 is a full pan MC receptor agonist (ie, a full agonist against MC 1 , MC 3 , MC 4 , and MC 5 ) and, similar to many other MCs, lacks agonist activity against MC 2 ( Table 1).…”

Section: Ap214 Is a Pan Agonist At Human MC Receptorsmentioning

confidence: 92%

“…We and others have proposed exploitation of endogenous anti-inflammatory pathways to develop new drugs, reasoning that this pharmacologic strategy, mimicking the natural course of resolving inflammation, would represent a novel therapeutic approach. [3][4][5] Among these natural anti-inflammatory and proresolving molecules are lipid mediators, such as lipoxins, resolvins, and protectins, as well as autacoids (eg, adenosine) and peptides, including annexin A1, galectin-1/9, and melanocortins (MCs).…”

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confidence: 99%

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The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 g/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC 1 , mutant mice but lost in MC 3 null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1␤, tumor necrosis factor-␣, and IL-6, respectively. Inhibition of IL-1␤ release was retained in MC 1 mutant cells but was lost in MC 3 null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC 3 null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Ap214 Is a Pan Agonist At Human MC Receptorsmentioning

confidence: 92%

mentioning

confidence: 99%

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The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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“…Furthermore, CTLA-4 increases T cell motility and overrides TCR induced stop signals required for stable conjugate formation between T cells and antigen presenting cells (APC) [7]. Critical importance of cAMP/protein kinase A (PKA) pathway for regulation of immune tolerance [8] is further supported by inability to develop T and B lymphocytes in mice conditionally deficient in PKA-RIa subunit (Dr. Hua Gu, Columbia University, personal communication). Moreover, overexpression of a newly established marker of T R cells termed G protein-coupled receptor (GPR) 83, inducible by cAMP in naive CD4 + CD25 -T cells, leads to the induction of regulatory Foxp3 + T cells in vivo [9,10].…”

Section: Introductionmentioning

confidence: 99%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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“…In an effort to identify such factors, many researchers have concentrated on traditional immunosuppressive cytokines, such as IL-10 and transforming growth factor-β1 (TGFβ1) [94]. Meanwhile, others have focused their search on neuropeptides and hormones, classically considered as neuroendocrine mediators, but which are also produced by immune cells, especially under inflammatory conditions [47]. …”

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confidence: 99%

Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders

et al. 2007

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The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. KeywordsInflammation; Autoimmunity; Regulatory T cells; Tolerance; Neuroimmunology; Neuropeptide Immune tolerance versus autoimmunityProtection against infection is fundamental to the survival of all complex organisms. The successful elimination of most pathogens requires crosstalk between the innate and adaptive arms of the immune system. The innate immune system recognizes pathogen-associated molecular signatures through pattern-recognition receptors, such as Toll-like receptors (TLRs), which induce the release of pro-inflammatory cytokines, chemokines and free radicals, the recruitment of inflammatory cells to the site of infection, and the lysis of infected host cells by natural killer cells and cytotoxic T lymphocytes. Although critical for the successful elimination of pathogens, the inflammatory process needs to be limited, since an excessive response can result in severe inflammation and collateral tissue damage. Inflammatory responses also increase the risk of inducing harmful autoimmune responses, where immune cells and the molecules that respond to pathogen-derived antigens also react to self-antigens. *Corresponding Author: Mario Delgado, Instituto de Parasitologia y Biomedicina, CSIC, Avd. Conocimiento, PT Ciencias de la Salud, Granada 18100, Spain. Phone: 34-958-181665. Fax: 34-958-181632. email: mdelgado@ipb.csic.es Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPeptides. Author manuscript; available in PMC 2008 September 1. Published in final edited form as:Peptides. 2007 September ; 28(9): 1833-1846. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Aut...

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Regulation of immune tolerance by anti-inflammatory neuropeptides

Cited by 206 publications

References 103 publications

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders

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