RESUMO
Interleukin-28A (IL-28A), IL-28B and IL-29 are a family of class II cytokines that stimulate antiviral responses through a heterodimeric receptor that is distinct from the type I interferon (IFN) receptor. To better understand how this newly described family of cytokines regulates the antiviral state, we compared various cellular responses elicited by IL-29 and IFN-alpha. Here we show that these cytokines stimulate similar patterns of signal transducer and activator of transcription 1 (STAT-1), -2, -3, and -5 phosphorylation and nearly identical patterns of gene expression when analyzed in two distinct cell types by microarray analysis. Interestingly, the IL-29 receptor is preferentially expressed on primary hepatocytes within normal liver and pegylated forms of IL-29 and IFN-alpha induced equivalent 2'5' oligoadenylate synthetase (OAS) and MX1 gene expression in this cell type. Pegylated IL-29 also produced a significant reduction in human hepatitis B and hepatitis C viral load in vitro and reduced the cytopathic effect caused by the fully replicating flavivirus, West Nile virus. In conclusion, IL-29 and IFN-alpha stimulate identical antiviral responses despite their utilization of different receptors. This fact, combined with significant receptor expression in hepatitis virus-infected livers, suggests that IL-29 may have therapeutic value against chronic viral hepatitis in human patients.
Assuntos
Antivirais/farmacologia , Citocinas/farmacologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Hepatite Viral Humana/tratamento farmacológico , Interferon-alfa/farmacologia , Interleucinas/farmacologia , Animais , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Células CHO/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Citocinas/uso terapêutico , Flavivirus/genética , Hepacivirus/genética , Vírus da Hepatite B/genética , Hepatite Viral Humana/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , RNA/análise , RNA/metabolismo , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT1/metabolismo , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: IL-31 is a newly discovered T-cell cytokine that, when overexpressed in mice, results in pruritus and skin dermatitis resembling human atopic dermatitis (AD). OBJECTIVE: We sought to investigate the expression of IL-31 and IL-31 receptor A (IL-31RA) in skin biopsy specimens and peripheral blood cells from patients with AD and healthy individuals. METHODS: Expression of IL-31 and IL-31RA was evaluated in skin biopsy specimens from patients with AD and healthy individuals by means of immunohistochemistry and RT-PCR. IL-31 protein production by skin-homing cutaneous lymphocyte antigen (CLA)-positive T cells was also assessed. RESULTS: IL-31RA protein was expressed by keratinocytes and infiltrating macrophages in skin biopsy specimens from patients with AD. Comparisons between skin from patients with AD and healthy skin showed IL-31RA expression at higher levels on epidermal keratinocytes in AD samples. Infiltrating cells, more numerous in skin from patients with AD compared with that of healthy individuals, expressed IL31 mRNA. Histomorphometric analysis of these cells indicated they were of the lymphocytic lineage, with the majority of cells staining positive for CLA and CD3. IL31 mRNA and protein expression is largely restricted to CD45RO(+) (memory) CLA(+) T cells in peripheral blood of patients with AD and healthy volunteers. Moreover, circulating CLA(+) T cells from patients with AD, but not from patients with psoriasis, are capable of producing higher levels of IL-31 compared with CLA(+) T cells from healthy individuals. However, the average levels of IL-31 were not significantly different between patients with AD and healthy individuals. CONCLUSION: We provide evidence that IL-31 expression is associated with CLA(+) T cells and might contribute to the development of AD-induced skin inflammation and pruritus.
Assuntos
Dermatite Atópica/fisiopatologia , Interleucinas/metabolismo , Glicoproteínas de Membrana/análise , Receptores de Retorno de Linfócitos/metabolismo , Pele/imunologia , Linfócitos T/imunologia , Adulto , Antígenos de Diferenciação de Linfócitos T , Antígenos de Neoplasias , Dermatite Atópica/imunologia , Feminino , Humanos , Interleucinas/genética , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Psoríase/fisiopatologia , Receptores de InterleucinaRESUMO
Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity. In competition studies, unlabeled CGH is a potent competitor for (125)I-TSH binding, whereas unlabeled TSH does not compete for (125)I-CGH binding. Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone. Transgenic overexpression of GPHB5 in mice produces elevations in serum T(4) levels, reductions in body weight, and proptosis. However, neither transgenic overexpression of GPHA2 nor deletion of GPHB5 produces an overt phenotype in mice. In vivo administration of CGH to mice produces a dose-dependent hyperthyroid phenotype including elevation of T(4) and hypertrophy of cells within the inner adrenal cortex. However, the distinctive expression patterns and binding characteristics of CGH suggest that it has endogenous biological roles that are discrete from those of TSH.
