RESUMO
OBJECTIVE: Corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) axis activation leads to the production of hormones, such as adrenocorticotrophic hormone (ACTH) and the α-melanocyte stimulating hormone (α-MSH). Data regarding the role of these hormones in systemic lupus erythematosus (SLE) are scarce. In the present study we aim to evaluate the participation of this axis in the cutaneous involvement of SLE. METHODS: Seventeen SLE patients were clinically evaluated, and biopsies from affected and unaffected skin of these patients were compared with 17 healthy control individuals. Immunohistochemical analyses for CRH, ACTH, α-MSH, and MC-1R were performed, and the serum levels of α-MSH, IL-1, IL-1ra, IL-6, IL-10, IL-12p70, IL-17, TNF-α, and IFN-γ were measured. RESULTS: The affected skin of the SLE patients exhibited higher CRH expression in the deep dermis compared to the skin of the controls (p = 0.024), whereas the tissue expression of ACTH, cortisol, α-MSH and its receptor MC-1R were comparable in SLE patients and controls. Higher serum levels of IFN-γ (p = 0.041), TNF-α (p = 0.001) and IL-6 (p = 0.049) were observed in SLE patients compared with controls, while α-MSH levels were similar in both groups. CONCLUSION: The novel finding of elevated CRH expression solely in the affected skin deep dermis supports the notion of a cutaneous local dysfunction of the CRH-POMC axis in the pathogenesis of cutaneous SLE lesions.
Assuntos
Hormônio Adrenocorticotrópico/análise , Hormônio Liberador da Corticotropina/análise , Lúpus Eritematoso Sistêmico/patologia , Pele/patologia , alfa-MSH/análise , Adulto , Autoanticorpos/sangue , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Humanos , Hidrocortisona/sangue , Pessoa de Meia-IdadeRESUMO
Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α-MSH analogue [Nle4, DPhe7]-α-MSH (NDP-MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α-smooth muscle actin (α-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and α-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of α-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.
Assuntos
Lúpus Eritematoso Sistêmico/metabolismo , alfa-MSH/metabolismo , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/imunologia , Artrite/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , Terpenos/efeitos adversos , alfa-MSH/administração & dosagemRESUMO
We have shown previously that nitric oxide (NO) controls platelet endothelial cell adhesion molecule (PECAM-1) expression on both neutrophils and endothelial cells under physiological conditions. Here, the molecular mechanism by which NO regulates lipopolysaccharide (LPS)-induced endothelial PECAM-1 expression and the role of interleukin (IL)-10 on this control was investigated. For this purpose, N-(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg/day for 14 days dissolved in drinking water) was used to inhibit both constitutive (cNOS) and inducible nitric oxide (iNOS) synthase activities in LPS-stimulated Wistar rats (5 mg/kg, intraperitoneally). This treatment resulted in reduced levels of serum NO. Under this condition, circulating levels of IL-10 was enhanced, secreted mainly by circulating lymphocytes, dependent on transcriptional activation, and endothelial PECAM-1 expression was reduced independently on reduced gene synthesis. The connection between NO, IL-10 and PECAM-1 expression was examined by incubating LPS-stimulated (1 µg/ml) cultured endothelial cells obtained from naive rats with supernatant of LPS-stimulated lymphocytes, which were obtained from blood of control or L-NAME-treated rats. Supernatant of LPS-stimulated lymphocytes obtained from L-NAME-treated rats, which contained higher levels of IL-10, reduced LPS-induced PECAM-1 expression by endothelial cells, and this reduction was reversed by adding the anti-IL-10 monoclonal antibody. Therefore, an association between NO, IL-10 and PECAM-1 was found and may represent a novel mechanism by which NO controls endothelial cell functions.