The Anticytokine Neuropeptide α-Melanocyte-Stimulating Hormone in Synovial Fluid of Patients with Rheumatic Diseases: Comparisons with Other Anticytokine Molecules

Catania, Anna; Gerloni, Valeria; Procaccia, S; Airaghi, Lorena; Manfredi, Maria Grazia; Lomater, Claudia; Grossi, Luca; Lipton, James M.

doi:10.1159/000097183

Cited by 50 publications

(34 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous research has shown a-MSH production in the pituitary, central nervous system, placenta, certain endocrine organs, and "barrier" tissues of the skin and gastrointestinal tract (38,39). a-MSH occurs in plasma (1) and synovial fluid of patients with rheumatoid arthritis (11). These results, together with previous observations that a-MSH-binding sites are widespread (40), indicate that a-MSH is widely available to modulate inflammatory reactions.…”

Section: Discussionmentioning

confidence: 60%

Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

Star

Rajora

Huang

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

268

245

View full text Add to dashboard Cite

a-Melanocyte-stimulating hormone (a-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of a-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We measured NO and a-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon Y.a-MSH inhibited production of NO, as estimated from nitrite production and nitration of endogenous macrophage proteins. This occurred through inhibition of production of NO synthase II protein; steady-state NO synthase II mRNA abundance was also reduced. a-MSH increased cAMP accumulation in RAW cells, characteristic of a-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary c-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecule of a-MSH, was expressed in RAW cells, and tumor necrosis factor a increased production and release of cv-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor a can induce macrophages to increase production of c-MSH, which then becomes available to act upon melanocortin receptors on the same cells. Such stimulation of melanocortin receptors could modulate inflammation by inhibiting the production of NO. The results suggest that a-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.The neuropeptide a-melanocyte-stimulating hormone (a-MSH), a derivative of proopiomelanocortin (POMC), found in the pituitary, brain, skin, circulation, and other sites, has potent antiinflammatory activity. a-MSH reduces fever (1, 2) and the following: (i) acute inflammation caused by irritants or by local mediators, such as cytokines (3, 4); (ii) delayed hypersensitivity responses, a model of allergic reactions (5, 6); (iii) chronic inflammation (mycobacterium-induced arthritis) (7,8); and (iv) systemic inflammation (e.g., endotoxemia and sepsis) (8, 9). Although a-MSH antagonizes the actions of proinflammatory cytokines (1, 2, 4, 9, 10), the precise mechanism of its antiinflammatory action is unknown. a-MSH was recently identified in synovial fluid of patients with rheumatoid arthritis (11). Thus, a-MSH is produced at sites of inflammation, although the cell type(s) responsible is unknown.a-MSH functions via melanocortin (MC) receptors (12-18). There are five subtypes of MC receptors (MC-1 through MC-5). These receptors contain seven membrane-spanning domains typical of G-protein-coupled receptors, and are coupled to adenylate cyclase to generate cAMP. MC receptors are differentially expressed in a restricted distribution, with MC-1 identified in melanoma cells and melanocytes but not in brain, adrenal, or other tissues by mRNA blotting (12, 13).That a-MSH has a wide spectrum of antiinflammatory activity suggests that the peptide inhibits a critical agent or event that is common to multiple forms of inflammatio...

show abstract

Section: Discussionmentioning

confidence: 60%

Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

Star

Rajora

Huang

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

268

245

View full text Add to dashboard Cite

show abstract

“…The endogenous agonist a-melanocytestimulating hormone (aMSH), like other protective mediators, is released by immune cells to counterbalance proinflammatory signals, thus preventing excessive tissue damage (5,6). In line with the resolution of inflammation concept, therapeutics targeting MC 1 and MC 3 will then be acting by mimicking the body's own protective resources (7,8) and might be characterized by a lighter burden of side effects.…”

Section: Elanocortin (Mc) Receptors (Mc 1 -Mcmentioning

confidence: 99%

“…The Journal of Immunology, 2015, 194: 3381-3388. 5 ), a family of class A druggable G protein-coupled receptors (GPCRs), are attractive therapeutic targets for a number of conditions due to their wide distribution and diversity of physiological processes they regulate (1). MC 1 regulates UV light-induced skin tanning and other immune responses because of its expression on leukocytes.…”

mentioning

confidence: 99%

Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects

Montero‐Melendez

Gobbetti

Cooray

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

There is a need for novel approaches to control pathologies with overexuberant inflammatory reactions. Targeting melanocortin (MC) receptors represents a promising therapy for obesity and chronic inflammation, but lack of selectivity and safety concerns limit development. A new way to increase selectivity of biological effects entails the identification of biased agonists. In this study, we characterize the small molecule AP1189 as a biased agonist at receptors MC1 and MC3. Although not provoking canonical cAMP generation, AP1189 addition to MC1 or MC3, but not empty vector, transfected HEK293 cells caused ERK1/2 phosphorylation, a signaling responsible for the proefferocytic effect evoked in mouse primary macrophages. Added to macrophage cultures, AP1189 reduced cytokine release, an effect reliant on both MC1 and MC3 as evident from the use of Mc1r−/− and Mc3r−/− macrophages. No melanogenesis was induced by AP1189 in B16-F10 melanocytes. In vivo, oral AP1189 elicited anti-inflammatory actions in peritonitis and, upon administration at the peak of inflammation, accelerated the resolution phase by ∼3-fold. Finally, given the clinical efficacy of adrenocorticotropin in joint diseases, AP1189 was tested in experimental inflammatory arthritis, where this biased agonist afforded significant reduction of macroscopic and histological parameters of joint disruption. These proof-of-concept analyses with AP1189, an active oral anti-inflammatory and resolution-promoting compound, indicate that biased agonism at MC receptors is an innovative, viable approach to yield novel anti-inflammatory molecules endowed with a more favorable safety profile.

show abstract

“…Despite an increase in plasma concentrations of ·-MSH in certain infectious or inflammatory disorders [10,13] and evidence of descending modulatory reactions stemming from MSH peptide receptors within the brain [14], it is clear that, in the absence of any significant change in circulating peptides, the peptide produced at the site of an inflammatory process can exert its effects locally. Synovial production of ·-MSH in rheumatoid arthritis patients is a good example of such a local anti-inflammatory influence [15].…”

Section: ·-Msh and Mcrs In Celiac Mucosamentioning

confidence: 99%

Anti-Inflammatory Effects of α-Melanocyte-Stimulating Hormone in Celiac Intestinal Mucosa

Colombo¹,

Buffa

Bardella

et al. 2002

Neuroimmunomodulation

Self Cite

View full text Add to dashboard Cite

Objectives: The peptide α-melanocyte-stimulating hormone (α-MSH) possesses potent anti-inflammatory activities and has been previously implicated in the endogenous control of inflammatory reactions. The aim of the present research was to determine whether α-MSH and its receptors participate in a localized anti-inflammatory response in the duodenal mucosa of celiac patients. Methods: Three series of experiments were performed, using duodenal biopsy pairs from 53 adult celiac patients and 14 normal subjects, in order to determine: (1) mucosal immunoreactivity for α-MSH and melanocortin receptors (MCRs), and gene expression of α-MSH precursor pro-opiomelanocortin and MCRs; (2) α-MSH and inflammatory cytokine production by duodenal specimens in vitro, and the influence of synthetic α-MSH on such cytokine production, and (3) the influence of stimulation with gliadin (the subfraction of gluten that is toxic to patients with celiac disease) on α-MSH and cytokine production in vitro and the effect of α-MSH on gliadin-stimulated cytokine production. Results: Elements of a localized anti-inflammatory influence based on α-MSH and its receptors were found: duodenal mucosa showed immunostaining for α-MSH and two of its receptor subtypes, MC1R and MC5R. α-MSH and MC1R immunoreactivity was more intense in specimens from celiac patients. Release of interleukin 6 from gliadin-stimulated duodenal mucosa was inhibited by synthetic α-MSH in vitro. Conclusions: Presence of α-MSH and its receptors in celiac mucosa suggests the presence of a local reaction to control the inflammatory response elicited by gliadin. In selected cases of refractory celiac disease, treatment with exogenous peptides might be considered.

show abstract

The Anticytokine Neuropeptide α-Melanocyte-Stimulating Hormone in Synovial Fluid of Patients with Rheumatic Diseases: Comparisons with Other Anticytokine Molecules

Cited by 50 publications

References 0 publications

Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects

Anti-Inflammatory Effects of α-Melanocyte-Stimulating Hormone in Celiac Intestinal Mucosa

Contact Info

Product

Resources

About