Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice

Abstract

Integrity of the thymus during perinatal life is necessary for a proper maturation of the pituitarygonadal axis in mice and other mammalian species. Thus congenitally athymic (nude) female mice show significantly reduced levels of circulating gonadotropins, a fact that seems to be causally related to a number of reproductive derangements described in these mutants. Interestingly, a number of in vitro studies suggest that the thymic peptide thymulin may be involved in thymus-pituitary communication. To determine the consequences of low serum thymulin in otherwise normal animals, we induced short (8 days)-and long (33 days)-term thymulin deficiency in C57BL/6 mice by neonatally injecting (intraperitoneally) an anti-thymulin serum and assessed their circulating gonadotropin levels at puberty and thereafter. Control mice received an irrelevant antiserum. Gonadotropins were measured by radioimmunoassay and thymulin by bioassay. Both long-and short-term serum thymulin immunoneutralization resulted in a significant reduction in the serum levels of gonadotropins at 33 and 45 days of age. Subsequently, we injected (intramuscularly) an adenoviral vector harboring a synthetic DNA sequence (5′-ATGCAAGCCAAATCTCAAGGTGGATCCAACTAGTAG-3′) encoding a biologically active analog of thymulin, methionine-FTS, in newborn nude mice (which are thymulin deficient) and measured circulating gonadotropin levels when the animals reached 52 days of age. It was observed that neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and prevented the reduction in circulating gonadotropin levels that typically emerges in these mutants after puberty. Our results indicate that thymulin plays a relevant physiological role in the thymuspituitary-gonadal axis.

Effects of GnRH immunization on the reproductive axis and thymulin

“…injection of anti-FTS serum markedly reduced the serum activity of endogenous thymulin. Moreover, this inhibition lasted for at least 10 days (Goya et al 2007). The effective cycle was shorter than in rats actively immunized with GnRH, probably because of the difference in the reaction times of the thymus to passive immunization (antibody immunoneutralization) and to active immunization (antigen vaccination).…”

Interactions Between Reproductive and Immune Systems During Ontogeny: Roles of GnRH, Sex Steroids, and Immunomediators

“…These disturbances manifest themselves not only in the inhibited functions of the immune system but also in the impaired synthesis and secretion of neuropeptides and hormones of the hypothalamus, pituitary, and peripheral endocrine glands (Goya et al, 2004;Chapman et al, 2009;Zakharova, 2009). The impaired neuroendocrine functions can be modulated by thymic peptides (Goya et al, 2007). There is evidence that bacterial endotoxins and proinflammatory cytokines have influence on the GnRH system of newborns (Li et al, 2007).…”

“…Thymic peptides, thymulin in particular, correct these disturbances (García et al, 2005). Neonatal thymulin gene therapy in nude mice results in normalization of blood thymulin and gonadotropin levels at maturity (Goya et al, 2007). Thus, the hormonal hypofunction of the thymus during early ontogeny entails long-term or irreversible disturbances in the structure and functions of both immune and reproductive systems.…”

The Thymulin-Lactotropic Axis in Rodents: Thymectomy, Immunoneutralization and Gene Transfer Studies

“…Thus, it was observed that thymulin stimulates PRL release in dispersed rat pituitary cells [9], whereas others have reported that thymulin inhibits PRL release in incubated rat pituitary fragments [8]. Furthermore, we have found in in vivo studies that thymulin is an important player in the communication of the thymus with the gonadotropic, corticotropic and thyrotropic axes [13,14,15,16]. …”