Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells.

Laboratory of Immunology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 08/2004; 114(1):57-66.
Source: PubMed

ABSTRACT Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.

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    ABSTRACT: Export Date: 18 October 2014
    Advanced Pharmaceutical Bulletin 12/2014; 4(4):339-343. · 0.88 Impact Factor
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    ABSTRACT: Anorexia-cachexia syndrome develops during the advanced stages of various chronic diseases in which patients exhibit a decreased food intake, weight loss, and muscle tissue wasting. For these patients, this syndrome is a critical problem leading to an increased rate of morbidity and mortality. The present pharmacological therapies for treating anorexia-cachexia have limited effectiveness. The Japanese herbal medicine rikkunshito is often prescribed for the treatment of anorexia and upper gastrointestinal (GI) disorders. Thus, rikkunshito is expected to be beneficial for the treatment of patients with anorexia-cachexia syndrome. In this review, we summarize the effects of rikkunshito and its mechanisms of action on anorexia-cachexia. Persistent loss of appetite leads to a progressive depletion of body energy stores, which is frequently associated with cachexia. Consequently, regulating appetite and energy homeostasis is critically important for treating cachexia. Ghrelin is mainly secreted from the stomach, and it plays an important role in initiating feeding, controlling GI motility, and regulating energy expenditure. Recent clinical and basic science studies have demonstrated that the critical mechanism of rikkunshito underlies endogenous ghrelin activity. Interestingly, several components of rikkunshito target multiple gastric and central sites, and regulate the secretion, receptor sensitization, and degradation of ghrelin. Rikkunshito is effective for the treatment of anorexia, body weight loss, muscle wasting, and anxiety-related behavior. Furthermore, treatment with rikkunshito was observed to prolong survival in an animal model of cachexia. The use of a potentiator of ghrelin signaling, such as rikkunshito, may represent a novel approach for the treatment of anorexia-cachexia syndrome.
    Frontiers in Pharmacology 12/2014; 5:271.
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    ABSTRACT: Ghrelin and obestatin are two different peptides originated from the same gene isolated in the stomach. Numer-ous actions have been described where these two peptides are implicated in metabolism, appetite regulation, glucose lev-els regulation, and a wide range of systemic effects. In this article, we summarize (1) the cellular receptors implicated in ghrelin and obestatin effects; (2) the role of ghrelin and obestatin in metabolism and appetite regulation; (3) their role in the glucose homeostasis regulation and its implication in diabetes patho-physiology; (5) the effects of ghrelin and obes-tatin in regulation of normal angiogenesis and (6) their possible role in the regulation of diabetes-induced pathologic angi-ogenesis. GHRELIN Ghrelin is an acylated, 28-amino-acid peptide that pro-motes the release of GH in the hypothalamus. It is the natural ligand of the GHSR-1a receptor [1]. For it to act on the GHSR-1a ghrelin has an n-octanoic acid modification on serine 3 residue [2]. The ghrelin gene is located in chromosome 3 (3p25-26) [1], contains four preproghrelin-coding exons, and encodes a precursor of 117aa (preproghrelin) with 82% of homology between species [3]. As a result of alternative splicing of this gene, a 27 aa acylated peptide was identified with the same activity potency as ghrelin (des-Gln14-ghrelin) [4]. Another form of ghrelin, des-acyl ghrelin, exists at significant levels in both stomach and blood. This variant lacks the octanoyl chain in serine 3 and represents more than 90% of the circu-lating peptide [2, 4, 5]. In plasma, acyl ghrelin levels are 10– 20 fmol/ml while total ghrelin levels are 100–150 fmol/ml (including both acyl and non-acyl forms) [6, 7]. Several mi-nor forms of ghrelin were described with modifications on the peptide chain or on the acidic chain and are only present in low amounts [4, 8]. Some of these are independently pro-duced and regulated and their levels are not directly related to those of ghrelin [3]. Finally, in a posttranslational process, this gene can originate a 23 aa peptide named obestatin that has some different and even opposite actions than ghrelin [9].

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