Thursday, 13 March 2014

IL-6 Disrupts the GH→IGF-1 Axis in Autism

Regular readers of this blog will see that there is an underlying logic behind recent posts.  We know levels of the cytokine IL-6 are raised in autism and we know that high levels of IL-6 in mice produces a baby with autism and we know this can be reversed by giving IL-6 antibodies to the mother, prior to birth.
We also know from numerous previous posts that growth hormone (GH) and the growth factor IGF-1 are implicated in autism.  Both GH and IGF-1 are used in clinical trials for autism.

Today’s post draws all this together.  It turns out that IL-6 disrupts the GH-IGF-1 axis.  The hormone GH is supposed to control the release of IGF-1; so a little more GH should produce a little more IGF-1.  The problem is that the cytokine IL-6 disrupts this relationship.  In the presence of elevated amounts of IL-6, which is characteristic of autism, and regressive autism in particular, GH does not produce the expected increase in IGF-1; IGF-1 levels are actually reduced.
This is very important.
A great deal of money is being spent researching and developing IGF-1 based therapies for autism and Retts syndrome.  Perhaps a much better strategy would be to clear the disruption from the GH-IGF-1 axis, so that IGF-1 levels could be restored naturally.  This means reducing IL-6 levels and IL-6 mediated disruption. We already know how to do this, from previous posts.
Now for some supporting evidence:-
In the following study, IL-6 was given to healthy volunteers and the over the next 8 hours their levels of GH and IGF-1 were measured.

The study confirmed earlier observations that IL-6 infusion leads to increased circulating GH. Despite the increase in GH levels, the study demonstrated an IL-6 infusion-associated reduction in IGF-I. 


Coming back to mice being given IL-6 to produce autistic pups, Autism Speaks funded a very thorough post-doctoral study at Caltech that focused on understanding this very issue (in mice at least).  The study aimed to find out how IL-6 ends up causing autism.  The conclusion is very interesting and again comes back to endocrine changes and the disrupted GH-IGF-1 axis.

I rest my case. 

"Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the  pongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GHIGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development. 

Furthermore, we find an IL-6-dependent dysregulation of the GH-IGF axis in MIA placentas, characterized by decreased levels of GH and IGFI mRNA, with corresponding decreases in placental IGFI and IGFBP3 protein. The actions of GH are achieved through the stimulation of IGFI production in target tissues. In addition, GH regulates the activity of IGFI by altering the production of either facilitatory or inhibitory binding proteins, including the IGFI stabilizing protein, IGFBP3. This suggests that the decreased GH levels seen in MIA placentas leads to the observed downstream suppression of IGFBP3 and IGFI production. It is believed that IGFs in the maternal circulation do not enter the placenta, and therefore IGFs in the placenta are derived from the placental compartment itself We demonstrate that the changes in IGFI and IGFBP3 expression are mediated by IL-6. However, it is unclear whether decreases in placental GH and subsequent effects on IGF production are downstream of IL-6-specific STAT3 activation. IL-6 does modulate IGFI and IGFBPs in several tissues, including placenta and cord blood. Pro-inflammatory cytokines, including IL-6, decrease circulating and tissue concentrations of GH and IGFI. We observe that IL-6- mediated STAT3 activation is associated with the expected IL-6- mediated increase in SOCS3 expression, along with other acute phase genes. Factors like SOCS play an important role in the down-regulation of GH and GH signaling. Importantly, it is reported that IL-6 inhibits hepatic GH signaling through up-regulation of SOCS3. As such, it is possible that, in MIA placentas, maternal IL-6-induced STAT3 activation and downstream sequelae lead to suppression of placental GH levels, disruption of IGFI production and further consequences on maternal physiology, placental function and fetal development. Altered placental physiology and release of deleterious mediators to the fetus are important risk factors for the pathogenesis of neurodevelopmental disorders. Placental IGFI in particular regulates trophoblast function , nutrient partitioning and placental efficiency. Moreover, altered IGFI levels are associated with intrauterine growth restriction (IUGR) and abnormal development. Animal models of IUGR and intrauterine infection, where the immune insult is confined to the uteroplacental compartment, highlight the key role of placental inflammation in perinatal brain damage, involving altered cortical astrocyte development, white-matter damage, microglial activation, cell death and reduced effectiveness of the fetal blood–brain barrier. In addition, adult pathophysiology is subject to feto-placental ‘‘programming’’, wherein molecular changes that occur prenatally reflect permanent changes that persist throughout postnatal life. Interestingly, placental responses to maternal insults can potentiate sexually dimorphic effects on fetal development. Obstetric complications are linked to schizophrenia risk and to the treatment responses of schizophrenic individuals. Notably, a greater occurrence of placental trophoblast inclusions was observed in placental tissue from children who develop autism spectrum disorder (ASD) compared to non-ASD controls. Chorioamnionitis and other obstetric complications are significantly associated with socialization and communication deficitis in autistic infants. The characterization of placental pathophysiology and obstetric outcome in ASD and schizophrenic individuals will be useful for the identification of molecular mechanisms that underlie these disorders and for potential biomarkers for early risk diagnosis. In addition to the observed effects of IL-6 on placental physiology and its downstream effects on fetal brain development and postnatal growth, direct effects of IL-6 on the fetal brain are also likely. Maternal IL-6 can potentially cross the placenta and enter the fetus after MIA. Furthermore, IL-6 mRNA and protein are elevated and STAT3 is phosphorylated in the fetal brain itself following MIA, raising the obvious possibility that IL-6 acts directly on the developing brain to influence astrogliosis, neurogenesis, microglial activation and/or synaptic pruning. However, recall that the identification of IL-6 as a critical mediator of MIA is based on maternal co-injection of poly(I:C) and anti-IL-6 blocking antibody, in addition to experiments inducing MIA in IL-6 KO animals. As such, in considering which pool(s) of IL-6 (e.g. maternal, placental, fetal brain, fetal periphery) is the ‘‘critical mediator’’, it will be important to understand the potential interaction between maternal IL-6 and fetal brain IL-6 expression. While we believe that the endocrine changes triggered by maternal-IL-6 signaling in the placenta reported here are important for fetal growth, it will be crucial to assess the potential impact of these placental changes on offspring behavior and neuropathology. We are currently exploring the effects of MIA in targeted IL-6Ra KOs in order to tie tissue- and cell-specific IL-6 activity to the manifestation of schizophrenia- and autism-related endophenotypes."

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