Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells

Abstract

The present study examined the effects of the androgen steroid, dihydrotestosterone (DHT), on murine T-cell production of a number of lymphokines. Direct exposure of murine T cells to DHT in vitro was found to reduce the amount of interleukin-4 (IL-4), IL-5, and gamma- interferon (gamma IFN) produced after activation with anti-CD3 without affecting the production of IL-2. Exposure of T cells to either androstenedione or testosterone (the metabolic precursors of DHT) affected no change in the biosynthesis of either of these lymphokines. We have determined that macrophages possess 5 alpha-reductase, and are thus competent to metabolize testosterone to DHT. This physicochemical information is complemented by a functional analysis of macrophage metabolism of testosterone. By incubating bone marrow macrophages with testosterone, before their use as accessory cells, the IL-4 and IL-5 producing potential of the activated T cells cocultured with them was depressed. That the observed effect was mediated by the conversion of testosterone to DHT was further corroborated by illustrating that the inhibition of IL-4 production was abrogated if 4MA, a specific 5 alpha- reductase inhibitor, was added to macrophage cultures containing testosterone. The biologic role of DHT in lymphokine and immune response regulation in vivo was addressed using several lines of investigation. First, transdermal delivery of DHT to groups of mice altered the capacity of T cells residing in the draining lymph nodes, only, to produce lymphokines. Second, treatment of either aged mice or the T cells isolated from them with a combination of dehydroepiandrosterone and DHT restored the capacity of their T cells to produce IL-2, IL-4, and gamma IFN to levels equivalent to that of younger mice. Finally, we observed a difference between males and females of a given age to produce IL-2, IL-4, and gamma IFN, with both IL-4 and gamma IFN production being elevated in females. Collectively, our findings indicate that DHT, similar to other steroid hormones, may play an important role in lymphokine regulation in vivo.

The Effect of Testosterone on Cytokine Production in the Specific and Non‐specific Immune Response

“…Moreover, in accordance with our previous study 8 we found no differences in IFN‐ γ production by both Th and Tc lymphocytes between untreated samples and samples treated with testosterone. This is in line with results from Araneo et al who also showed no changes in synthesis of IFN‐ γ and IL‐2 by murine T cells exposed to testosterone 14 …”

Maternal testosterone in pregnancy and atopic outcomes in childhood

“…One might anticipate, however, that effects of maternal testosterone on the cytokine milieu would be more pronounced in the absence of maternal atopic disease, as maternoplacental cytokine production is likely to be less markedly Th2 skewed and over‐riding in this situation, and this is what we found. Support for a downregulating effect of testosterone on Th2 cytokines comes from studies of adult mice which have shown that DHEA in vivo , and the metabolite of testosterone, dihydrotestosterone, in vitro , reduce levels and expression of interleukin (IL)‐4, IL‐5, IL‐6 and IL‐10 (11, 12, 40, 41). Data are conflicting on the effects of these androgens on the Th1 cytokines interferon‐ γ and IL‐2 (12, 40, 41).…”

Gonadotropin treatment restoresin vitrointerleukin-1β and tumour necrosis factor-α production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism

“…Additionally, a high level of IL‐4 production is reported in androgen resistance [48]. It has also been shown that dihydrotestosterone exerts a depressive effect on the production of IL‐4 by activated murine T cells [49]. IL‐2 is a mediator produced chiefly by the Th1 subset of helper/inducer T cells and stimulates other T cells, while IL‐4 is produced by Th2 cells and targeted to T and B cells.…”