ABSTRACT
Malignant pleural mesothelioma is a highly aggressive tumor arising from the mesothelial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treatments and appears to be very sensitive to growth-promoting influences of cytokines and growth factors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that alpha-melanocyte-stimulating hormone (alpha-MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endogenous inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleural effusions of patients with malignant mesothelioma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release alpha-MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high-affinity receptor for alpha-MSH. Immunoneutralization of MC1R in the cell lines enhanced expression of interleukin-8 (IL-8), IL-6, and transforming growth factor-beta. These molecules promote mesothelioma proliferation and are considered therapeutic targets in this tumor. Coincubation of mesothelioma cells with synthetic alpha-MSH significantly reduced cell proliferation. The present research shows an autocrine-inhibitory circuit based on alpha-MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothelioma cell proliferation by taking advantage of this endogenous inhibitory circuit.
Subject(s)
Autocrine Communication/physiology , Mesothelioma/pathology , Pleural Neoplasms/pathology , alpha-MSH/physiology , Cell Division , Cytokines/biosynthesis , Dose-Response Relationship, Drug , Humans , Immunohistochemistry , Mesothelioma/metabolism , Peptide Fragments/pharmacology , Pleural Neoplasms/metabolism , Pro-Opiomelanocortin/genetics , RNA, Neoplasm/analysis , Receptor, Melanocortin, Type 1/analysis , Tumor Cells, Cultured , alpha-MSH/chemistryABSTRACT
BACKGROUND: With the increasing need for organ transplantation and the use of "marginal" organs, novel approaches are sought to increase the efficiency and survival of transplanted tissue. We tested the idea that treatment with the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous hormone that does not cause marked immunosuppression but does reduce reperfusion injury, may protect allografts and prolong their survival. METHODS: Donor cardiac grafts (Brown Norway) were transplanted heterotopically into the abdomen of recipient (Lewis) rats. Treatments consisted of intraperitoneal injections of Nle DPhe -alpha-MSH (NDP-alpha-MSH) or saline from the time of transplantation until sacrifice or spontaneous rejection. Allografts were removed on day 1, day 4, or at the time of rejection and examined for histopathology and expression of molecules prominent in reperfusion injury, transplant rejection, and apoptosis. RESULTS: NDP-alpha-MSH treatment caused a significant increase in allograft survival and a marked decrease in leukocyte infiltration. Expression of molecules such as endothelin 1, chemokines, and adhesion molecules, which are involved in allograft rejection, was significantly inhibited in NDP-alpha-MSH-treated rats. CONCLUSIONS: The results indicate that protection of the allograft from early injury with alpha-MSH can postpone rejection. Addition of this early protection with the peptide to usual treatment with immunosuppressive agents may, therefore, improve success of organ transplants.
Subject(s)
Graft Rejection/drug therapy , Graft Survival/drug effects , Heart Transplantation , alpha-MSH/pharmacology , Animals , Chemokine CCL2/genetics , Chemokine CCL5/genetics , Endothelin-1/genetics , Fas Ligand Protein , Gene Expression/drug effects , Graft Rejection/immunology , Graft Rejection/pathology , Graft Survival/immunology , Intercellular Adhesion Molecule-1/genetics , Interferon-gamma/genetics , Interleukin-1/genetics , Male , Membrane Glycoproteins/genetics , Nitrates/blood , Nitric Oxide/blood , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Nitrites/blood , Proto-Oncogene Proteins c-sis/genetics , Rats , Rats, Inbred BN , Rats, Inbred Lew , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1 , Transplantation, Homologous , Tumor Necrosis Factor-alpha/genetics , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
OBJECTIVES: The peptide alpha-melanocyte-stimulating hormone (alpha-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 alpha-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 alpha-MSH and melanocortin receptors (MCRs), and gene expression of alpha-MSH precursor pro-opiomelanocortin and MCRs; (2). alpha-MSH and inflammatory cytokine production by duodenal specimens in vitro, and the influence of synthetic alpha-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 alpha-MSH and cytokine production in vitro and the effect of alpha-MSH on gliadin-stimulated cytokine production. RESULTS: Elements of a localized anti-inflammatory influence based on alpha-MSH and its receptors were found: duodenal mucosa showed immunostaining for alpha-MSH and two of its receptor subtypes, MC1R and MC5R. alpha-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 alpha-MSH in vitro. CONCLUSIONS: Presence of alpha-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.
