RESUMO
Sex chromosome complement, by determining whether an ovary or testis develops, exerts indirect hormone-mediated effects on the development of sex-specific traits. However, this does not preclude more direct effects that are independent of gonadal hormones. To look for gonadal hormone-independent effects in sexually dimorphic immune responses, we used mice in which the testis determinant Sry has been moved from the Y chromosome to an autosome, thus allowing the production of mice that differ in sex chromosome complement while having the same gonadal type. This model permits comparison of XX and XY mice with ovaries or testes. These mice were immunized with an autoantigen, and draining lymph node cells were assessed for autoantigen-specific proliferative responses and cytokine production. Surprisingly, we found that the male complement of sex chromosomes (XY) was relatively stimulatory, whereas male sex hormones were inhibitory, for this immune response. This is the first experimental evidence of a compensatory yin-yang effect of sex chromosome complement and sex hormones on a biologic process.
Assuntos
Proteínas do Sistema Complemento/genética , Hormônios Esteroides Gonadais/genética , Hormônios Esteroides Gonadais/imunologia , Cromossomo X , Cromossomo Y , Animais , Sequência de Bases , Primers do DNA , Proteínas de Ligação a DNA/genética , Feminino , Genótipo , Masculino , Camundongos , Proteínas Nucleares/genética , Orquiectomia , Ovariectomia , Processos de Determinação Sexual , Proteína da Região Y Determinante do Sexo , Testículo/anatomia & histologia , Fatores de Transcrição/genéticaRESUMO
Estrogen treatment has been found to be protective in experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS). We investigated whether the effect of estrogen treatment is gender-specific. Estrogen receptor (ER) expressions, ERalpha and ERbeta, were found to be equivalent in both genders. EAE disease severity in both females and males was decreased with estriol treatment as compared to placebo. Finally, proinflammatory cytokine production during autoantigen-specific immune responses was decreased with estriol treatment in both females and males. These data support a potential role for estriol treatment for men in addition to women with MS.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Estriol/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Caracteres Sexuais , Análise de Variância , Animais , Técnicas de Cultura de Células , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/complicações , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Glicoproteínas/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , RNA Mensageiro/biossíntese , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de TempoRESUMO
A gender difference prevails in some murine strains of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Our results showed that castration of SJL males, a strain characterized by decreased susceptibility of males as compared to females, displayed increased disease severity. In contrast, castration had no effect on disease in C57BL/6 males, a strain in which no gender difference in EAE is observed. Regardless of whether endogenous androgens were protective in a given genetic background, supplemental androgen treatment was protective in gonadally intact males of both strains. These data provide a basis for the novel therapeutic use of supplemental testosterone for men with MS.
