The role of interleukin-10 in mediating the effect of immune challenge on mouse gonadotropin-releasing hormone neurons in vivo

Abstract

Immune challenge alters neural functioning via cytokine production. Inflammation has profound impact on the central regulation of fertility, but the mechanisms involved are not clearly defined. The anti-inflammatory cytokine interleukin (IL)-10 is responsible for balancing the immune response in the brain. To examine whether IL-10 has an effect on the function of the gonadotropin-releasing hormone (GnRH) neurons, we first examined the effect of immune responses with distinct cytokine profiles, such as the T-cell-dependent (TD) and T-cell-independent (TI) B-cell response. We investigated the effect of the TD and TI immune responses on ERK1/2 phosphorylation in GnRH neurons by administering fluorescein-isothiocyanate/keyhole-limpet-hemocyanin (KLH-FITC) or dextran-FITC to female mice. Although dextran-FITC had no effect, KLH-FITC induced ERK1/2 phosphorylation in GnRH neurons after 6 days. KLH-FITC treatment increased the levels of IL-10 in the hypothalamus, but this treatment did not cause lymphocyte infiltration or an increase in the levels of pro-inflammatory cytokines. In IL-10 KO mice, KLH-FITC-induced ERK1/2 phosphorylation in the GnRH neurons was absent. We also showed that in IL-10 KO mice, the estrous cycle was disrupted. Perforated patch-clamp recordings from GnRH-GFP neurons, IL-10 immunohistochemistry and in vitro experiments on acute brain slices revealed that IL-10 can directly alter GnRH neuron firing and induce ERK1/2 phosphorylation. These observations demonstrate that IL-10 plays a role in influencing signaling of GnRH neurons in the TD immune response. These results also provide the first evidence that IL-10 can directly alter the function of GnRH neurons and may help the maintenance of the integrity of the estrous cycle.

Significance statement The anti-inflammatory cytokine interleukin (IL)-10 plays a role in maintaining a balanced immune response in the brain. Although clinical studies have demonstrated that IL-10 influences fertility, the impact of IL-10 on gonadotropin-releasing hormone (GnRH) neurons is unknown. Our results demonstrate that T cell-dependent (TD) immune challenge induces ERK1/2 phosphorylation in GnRH neurons via IL-10. We provide the first evidence that IL-10 directly regulates the firing and signaling of GnRH neurons. Our results indicate that IL-10-induced ERK1/2 phosphorylation in GnRH neurons might be associated with the maintenance of the estrous cycle in bacterial/viral infection.