Signalling pathway

Article Index

Preface

In former times, when toxicologists wanted to find out whether a hazardous substance was suitable to trigger a certain health damage they were forced to review so-called “toxicological profiles” to learn whether this health damage was listed there as typical effect of a toxicity with this hazardous substance.

For a long time it was unknown whether, and if so, how these listed health disorders or health damages that differed extremely with regard to their point of action in the organism were causally linked to each other.

The toxicologists were never sufficiently confident that a concrete health damage could definitely be ascribed to a certain exposure to a hazardous substance.

That changed with the discovery of the aryl hydrocarbon receptor by Poland (and others) in 1972 and the relevant findings that have been continuously increasing to date. Over the decades, the receptor toxicology has established itself as individual and independent human-toxicological area of expertise.

In plain language, the signalling pathway of the Ah receptor presents a knock-on effect that principally triggers the same reactions after a suitable hazardous substance, e.g., dioxin or the softening agent bisphenol-A has docked to the receptor.

One of these always identical reactions causes a certain gene sequence in the cell to be transcribed, which entails an increased production of a certain enzyme (CYP450). The more toxic a hazardous substance, the higher the activity of the CYP450 enzyme. This basic principle is applied in every examination of food or consumer goods suspected of being contaminated with dioxins.

On the basis of this principle, the same neurological and cardiovascular health impairments develop after a correspondingly strong activation of the Ah receptor. The same applies to changes of the immune and detoxification systems (glutathione-S-transferase) that can be diagnosed by laboratory tests, and to pathological organ changes, primary target organs: heart, liver, brain, and lungs.

Although each of these diagnoses is listed as typical damage effect in the internationally recognized toxicological profiles of these hazardous substance groups (polycyclic / aromatic halogen hydrocarbons), the causal relation between exposure and health damage has been questioned or denied by the interested parties.

The findings connected with the discovery of the aryl hydrocarbon receptor signalling pathway can put an end to this situation.

The causal relation between cause (hazardous substance) and effect (health damage) could doubtlessly be broken down to the last detail with the help of this basic principle ‘AhR signalling pathway’.

Hereinafter, we will try to describe the partly rather complicated AhR signalling pathway in a most general and comprehensive way, subdivided in stages.

First stage: Contact

The so-called aryl hydrocarbon receptor signalling pathway as basic principle for the understanding of the causal relation between hazardous substance and health damage.

According to Wikipedia, the aryl hydrocarbon receptor is a protein found in the cell envelope (cytosol) and the cell nucleus of vertebrate cells that is involved in the control / programming of the gene activity as “transcription factor”.

Simply put, a transcription factor serves to change the gene functions or to transcribe their programs.

As early as at the beginning of the 20th century it was known that certain chemicals, heavy metals as well as radioactive radiation were capable of triggering gene damage. Now we know how this works.

After the aryl hydrocarbon receptor (AhR) has been activated by a corresponding ligand (chemical or heavy metal), it travels together with the toxin from the cell surface to the cell nucleus. Another protein, the “aryl hydrocarbon receptor nuclear translocator” (ARNT) ensures that the AhR can connect to the ligand.

On its way, this trio composed of ligand (dioxin), AhR, and ARNT carries a third protein called heatshock protein 90 (HSP90) to the cell nucleus without binding tightly to it.

Having reached the cell nucleus, the trio separates from the HSP90 and heads for a certain point at the double helix of our genome, called Dioxin Response Element (DRE). Note: Some authors refer to DRE as “xenobiotic responsive element” (XRE).

Having reached the DRE or XRE, the AhR / ARNT / ligand trio docks with the dioxin response element and thereby causes a genetic program change corresponding to the potential of the hazardous substance / ligand. The genetic program change is part of our detoxification system.

On the one hand the massive activation of the Ah receptor results in a negative change of both the genetic constitution in the area of the glutathione-S-transferase (GST) and its enzyme activity, i.e., this latter is permanently downregulated in case of a correspondingly strong (dioxin) exposure.

On the other hand, a massive increase of the enzyme activity in the area of the cytochrome P450 entails a likewise massive production of free oxygen radicals (Reactive Oxygen Species - ROS).

The same is true for the heatshock protein 90 that had travelled from the cell envelope to the cell nucleus together with the AhR / ARNT / ligand trio. This protein too, primarily induces the distribution of free oxygen radicals.

Free oxygen radicals are extremely reactive.

The organism uses this fact by opposing hazardous substances such as polycyclic aromatic halogen hydrocarbons or halogen hydrocarbons consisting of - as their names suggests - long-chain hydrocarbon compounds to free oxygen radicals.

The contact with free oxygen radicals causes a break of these long-chain compounds into shorter ones that are much less toxic and can now be metabolized by the (human) organism via the liver and then be eliminated via the kidneys or faeces.

However, there are two snags:

First: Unfortunately, the free oxygen radicals are incapable of breaking pentachloro dibenzodioxin (PeCDD) or Seveso dioxin TCDD.

Second: The chronic increase of cytochrome P450 and the presence of the heatshock protein 90 entails a permanent increase of the free oxygen radicals, which subsequently leads to further genetic changes, i.e., severe health damage, particularly in the area of the immune system (autoimmune diseases) and the pathogenesis of cancer.

Start AhR signalling pathway

Second stage: Immune system

The exploration of the AhR signalling pathway explains the interactions between the activation of the aryl hydrocarbon receptor and the human immune system.

Depending on the hazardous substance, the cascade of events triggered by the activation of the dioxin receptor in the area of the immune system ranges from an immediate reaction of the immune system (skin reaction) via the autoimmune diseases referred to as civilization diseases up to organ failure (e.g., heart, liver) or lethal cancerous diseases.

In the case of suspected diabetes, for instance, an attending physician (or medical specialist) solely arranges for the laboratory tests that are required for the diagnosis itself.

The investigation on the pathogenesis (development of the disease) of an autoimmune disease, in contrast, requires the determination of all changes that can be detected by laboratory tests.

This includes further parameters in addition to the immune system, e.g., the hormone and detoxification systems as well as metabolic disorders, but also the interaction with other receptors. (More information will follow).

A comparison of the diabetes-typical, i.e. extremely specific derailment described by Honkanen et al in the Journal für Immunologie (journal of immunology) 2010 with the one outlined by Bellemore and colleagues in the Journal für klinische experimentelle Immunologie (journal of clinical and experimental immunology) published in 2015 clearly shows that the changes of the laboratory values depicted by the author groups are extremely similar to each other:

Hokanen et al,
IL-17 immunity in human type 1 diabetes
JImmunol. 2010 Aug 1;185(3):1959-67
https://www.ncbi.nlm.nih.gov/pubmed/20592279
http://www.jimmunol.org/content/185/3/1959.full-text.pdf

Bellemore et al
Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice.
Clin Exp Immunol. 2015 Dec;182(3):261-9. doi: 10.1111/cei.12691. Epub 2015 Sep 22.
https://www.ncbi.nlm.nih.gov/pubmed/26250153
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636888/pdf/cei0182-0261.pdf

The immune system in detail

The activation of the Ah receptor entails a correspondingly high production / distribution of native (non-programmed) T cells (Treg cells) in the spinal marrow (namely in proportion to the triggering hazardous substance) that cause - as a first reaction - a painful inflammatory process at the production site (spinal marrow in the lumbar spine region).

The distribution of native T cells leads to a humoral immune response that not only manifests itself by a massive increase of the macrophages and a reduction in the number of helper cells (CD4) and an increase of the killer cells (CD8), but also in an increase of the interleukine production values (Il17,IL21,IL22).

In a next step, i.e., an immune system cascade of events following to an AhR activation, B cell receptors are addressed. This leads to a substance-specific increase or reduction of the corresponding immunoglobulins. (B cells are antibodies (proteins) that are produced by B lymphocytes and directed against certain components of the antigen).

Note: The Seveso dioxin TCDD downregulates the immunoglobulin M secretion in activated B cell lines (CH12.LX), whereas this dioxin action is absent in a B cell line that was pretreated with lipopolysaccharides, a molecular group (fat and sugar) that is widespread in nature.
https://www.ncbi.nlm.nih.gov/pubmed/9547351

It was found only recently that the aryl hydrocarbon receptor (in case of a toxicity) is absolute necessary for the optimal B cell proliferation. The Ah receptor interacts directly with the B cell receptors and regulates them (in the best case).
https://www.ncbi.nlm.nih.gov/pubmed/9547351 www.ncbi.nlm.nih.gov/pmc/articles/PMC5210087/pdf/EMBJ-36-116.pdf

In his article titled “Aryl Hydrocarbon Receptor Control of Adaptive Immunity“ published in the Pharmacological Review in October 2013, the author Franzisco J. Quintana presents the far-reaching connections of the aryl hydrocarbon receptor signalling pathway including its interactions with other receptors with the precision of a standard work.

His summary should be followed:

»In conclusion, the AhR controls important immune processes in response to endogenous and environmental cues. Consequently, the AhR and its signaling pathway offer plausible molecular mechanisms through which environmental and endogenous ligands may control immunity and autoimmunity while providing us with new opportunities for targeted, therapeutic modulation of the immune response.«

Aryl Hydrocarbon Receptor Control of Adaptive Immunity
Francisco J. Quintana and David H. Sherr
Pharmacol Rev 65:1148–1161, October 2013
http://pharmrev.aspetjournals.org/content/pharmrev/65/4/1148.full.pdf

Graph from "The Role of AhR in Autoimmune Regulation Int J Mol Sci 2014 15 10116-10135"
Published in "International Journal of Molecular Sciences — Open Access Journal"

ahr_role_in_autoimmune_regulation

Aryl hydrocarbon receptor (AhR) signalling pathway

Article Index

Preface

First stage: Contact

Second stage: Immune system

Further reading on this subject:

The immune system in detail