The release of activin A in response to intravenous injection of the bacterial cell-wall component lipopolysaccharide (LPS) was investigated in an ovine model of acute inflammatory challenge in newborn and adult sheep, and in non-pregnant and pregnant ewes. Neonatal lambs (<20 days of age) showed a quantitatively similar response in terms of circulating concentrations of activin A, its binding protein follistatin and the cytokine interleukin-6 compared with adult ewes challenged with an equivalent dose (300 ng/kg bodyweight) of LPS. The fever response and plasma tumour necrosis factor-α release in response to LPS, however, were significantly (P < 0.01) less in lambs than in the adult group. Pregnant ewes in the last trimester of gestation had similar responses to LPS, in all aspects measured, compared with their non-pregnant counterparts, apart from an ablated fever response. Although the adult and neonatal sheep responded to LPS, a similar response was not apparent in the fetal circulation, possibly due to a protective effect of the placenta. A 10-fold increase in the dose of LPS (from 300 ng to 3 μg/kg bodyweight) given to neonatal lambs elicited an increase in several cytokine responses measured, with a significant (P< 0.05) increase in follistatin release. In contrast, the amount of activin released by the increased dose of LPS was similar to that invoked by the lower dose. The effect of tolerance to LPS was investigated by giving a second challenge of LPS 5 days after the initial injection. In all animals studied, there was an ablated (P < 0.05) response to the subsequent LPS injection, apart from a similar temperature-response profile. These data provide further evidence that activin A concentrations in the bloodstream are acutely responsive to inflammatory challenge in post-natal life and suggest that the response forms a significant component of the innate immune system.

In several biological systems, the inhibin β_A homodimer activin A is stimulated by, and in turn, inhibits the action of interleukin (IL)-1 (both IL-1α and IL-1β) and IL-6. The possibility that a similar regulatory relationship operates within the testis was investigated. Sertoli cells from immature (20-day-old) rats were cultured with human IL-1α or IL-1β, human IL-6 and/or ovine FSH or dibutyryl cAMP. Activin A and the inhibin dimers, inhibin A and inhibin B, were measured by specific ELISA. Immunoreactive inhibin (ir-inhibin) was measured by RIA. Activin/inhibin subunit mRNA expression was measured by quantitative real-time PCR. Both IL-1 isoforms, but not IL-6, stimulated activin A secretion through increased synthesis of β_A-subunit mRNA. IL-1 also stimulated activin A secretion by testicular peritubular cells. In contrast to the effect on activin A, IL-1 suppressed inhibin β_B-subunit and, to a lesser extent, α-subunit mRNA expression, thereby reducing basal and FSH-stimulated inhibin B secretion by the Sertoli cells. Conversely, FSH inhibited basal activin A secretion and antagonised the stimulatory effects of IL-1. Dibutyryl cAMP partially inhibited the action of IL-1 on activin A secretion, but had no significant effect on basal activin A secretion. Secretion of inhibin A was low in all treatment groups. These data demonstrate that IL-1 and FSH/cAMP exert a reciprocal regulation of activin A and inhibin B synthesis and release by the Sertoli cell, and suggest a role for activin A as a potential feedback regulator of IL-1 and IL-6 activity in the testis during normal spermatogenesis and in inflammation.

The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24–28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r ²=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.