Sport inhibits IDO, maybe a basis for PEM?

[pattismith]

Kynurenine and IDO: Immunological Markers and Actors
Author(s): Karl-Heinz Kellner1; Anastasia Stemke2
1Haid-und-Neu-Straße 7 - 76131 Karlsruhe, Germany ; 2Immundiagnostik AG Stubenwald-Allee 8a 64625 Bensheim, Germany ; Correspondence: kk@drkellner.de


https://isom.ca/article/kynurenine-ido-immunological-markers-actors/

Citation: Kellner KH, Stemke A (2018) Kynurenine and IDO: Immunological Markers and Actors. J Orthomol Med. 33(3)

Summary and A Look Ahead


Our health and ability to overcome disease are decisively dependent on immune balance. This balance is driven primarily by the activity of indolamin 2,3-dioxygenase. High IDO activity and high kynurenine levels pull a virtual immune blockade along with it.


Clinical studies show that a dysregulation of IDO activity is followed with worse prognoses in infections or malignant diseases.
On the other hand, studies show that in addition to classical treatment, sports activity or natural substances may be of advantage to decrease IDO activity in these diseases.


IDO activity as well as the level of kynurenine can easily be determined using measurement of kynurenine and tryptophan in serum or plasma, offering a meaningful diagnostic approach for prevention and treatment follow-up.​

Introduction

The human organism is constantly exposed to numerous immunological stimuli, to which it must respond with appropriate feedback. For a successful defence a balance must be achieved between activity and overreaction of the immune system.

An underactivity of the immune system allows pathogens that have entered or malignant cells that have formed, to stay. Overreaction of the immune system leads to autoimmune reactions.

The products of kynurenine metabolism are important regulators of the immune balance. The main enzyme in kynurenine metabolism, indolamin 2,3-dioxigenase (IDO), and its main agent kynurenine, are discussed in this review article.

Biochemical Basis


Tryptophan metabolism along with the kynurenine pathway play an essential role in the regulation of the immune system. Approximately 95% of absorbed tryptophan is degraded via this pathway (Beadle, et al. 1947).


The rate-limiting enzymes of the kynurenine pathway are indolamin-2,3-dioxygenases, including isoforms 1 and 2, and tryptophan 2,3-dioxigenase. The enzymes catalyze the degradation of tryptophan to unstable n-formyl kynurenine, finally resulting in kynurenine.


IDO 1, important for the prevention of immune overreaction, is present in all tissues and immune cells which come into contact with the outside world and plays an important role in the control of immunity, mainly in immune cells such as macrophages as well as dendritic cells.

Formation of IDO 1 is induced by several factors, such as lipopolysaccharides (Fujigaki, et al. 2001), inflammatory cytokines INF-alpha (Hassanain, et al. 1993), INF-gamma (Taylor, et al. 1991) or tumor necrosis factors (TNF alpha) (Babcock, et al. 2000) with the participation of the corresponding receptors. However, it can also be induced via the so called aryl hydrocarbon receptor (AHR) through toxic substances (Busbee, et al. 2013) or in a positive feedback via products of the kynurenine pathway (Orabona & Pallotta, 2012).


The influence of kynurenine on cytotoxic T cells or killer cells is noteworthy.


(I) The tryptophan depletion resulting from IDO activation in immune cells via the stress response kinase general control nonderepressible 2 kinase (GCN2) induces a G1 T cell arrest with decreased proliferation or apoptosis of killer cells (Munn, et al. 2005; Fallarino, et al. 2006; Manlapat, et al. 2007).


(II) The vitality of toxic T cells, regulatory T cells (Tregs), and antigen presenting cells (APCs) of the adaptive immune system are influenced. A high activity of IDO and an accompanying high kynurenine level shift the immune balance toward more Tregs and less cytotoxic T cells and, therefore, in the direction of immune tolerance (Puccetti, et al. 2007; Jasperson, et al. 2008). It should be noted that the main product of the IDO pathway, kynurenine, (i) is a ligand of the aryl hydrocarbon receptor, which modulates the immune response (Opitz, et al. 2011) and (ii) stimulates the production of IDO (Vogel, et al. 2008).


This can then lead to a downright vicious cycle following the induction of IDO 1:


(i) Various inductors activate IDO 1 in immune cells (dendritic cells and macrophages).


(ii) Immune cells steadily form kynurenine which supports its own production through positive feedback.


(iii) The effect of kynurenine on AHR results in an imbalance between Tregs and cytotoxic T cells.


This results in an imbalance of the immune system characterized by a high level of kynurenine at low levels of tryptophan and is self-perpetuating with a negative effect on health. In the following, we would like to underscore the clinical meaning of this imbalance using two clinical pictures.


.


Immune Tolerance and Infections


Viruses, bacteria, and fungi can have the unpleasant characteristic of being able to be dormant in the target organism over a longer period (months to years) without being significantly attacked by the immune system. This is called latent infection. The disease is not cured completely.


Kynurenine plays a deciding role here. In the normal run of an infection the pro-inflammatory path of the immune system is initially activated. To prevent an overshooting immune response, an immune brake is activated by simultaneously activating the kynurenine pathway. This then leads to a fine-tuning of the pro- and anti-inflammatory factors as with kynurenine and a balancing of the immune system.


Following the infection, pro- and anti-inflammatory factors (immune block) return to original levels. If the immune block is maintained this is not the case. The activity of IDO and the level of kynurenine remain high. (Figure 5) The immune block remains active. However, if the activity of IDO remains high, infections cannot be combated effectively.


Already in 1991 the significance of the IDO pathway in HIV was discussed. IDO activity and the level of kynurenine increase as a consequence of HIV infection (Fuchs, et al. 1991; Huengsberg, et al. 1998; Werner, et al. 1998). At the same time it was proven that the number of cytotoxic T cells is reduced in patients with high levels of kynurenine. This worsens the chance of survival for patients (Bipath, et al. 2015).


Analogous to this, it was recently observed that in other viral infections, such as cytomegaly, Epstein-Barr, HBV and HBC or influenza, a suppression of the immune system is mediated via IDO activity. Figure 6 shows an example of the inhibition of CMV- specific cytotoxic T-cells (so called CD8+ T-cells) via IDO activation (Hong, et al. 2016).


In the following clinical study the effect of a possible immune block was proven due to high IDO activity or high kynurenine level in a patient with pneumonia (Suzuki, Y. et al. 2012). The above Kaplan-Mayer diagram shows a clear worse prognosis when the kynurenine level is high.


.


Immune Tolerance and Cancer


All types of cancer cells can express IDO and create an immunosuppressive environment by synthesizing kynurenine, leading to apoptosis of killer cells and acquisition of T regulatory cells. Figure 3 shows a model of immunosuppression via IDO activation and the formation of kynurenine on the cellular level.


This hypothesis is supported by numerous clinical studies and their significant results are summarized in the following:


• High IDO activity supports the development of cancer with a hazard-ratio of 20%. This was shown in a study including more than 7015 patients (Zuo, et al. 2016).


• High IDO activity complicates the recovery in the course of cancer and increases the risk of relapse in most types of cancer. Examples include colorectal cancer (Cavia-Saiz, et al. 2014), lung cancer (Creelan, et al. 2013; Chuang, et al. 2014) Leukemia (Folgiero, et al. 2014), Hodgkin‘s Lymphoma (Choe, et al. 2014) as well as cervical cancer (Ferns, et al. 2015), etc.


A study by Creelan et al. impressively shows how IDO activity in cancer patients can be changed during treatment. Due to radiation and chemotherapy, the level of kynurenine increases in some patients. These patients must expect a worse prognosis (refer to Figure 8). Low levels of IDO activity or kynurenine are therefore of great significance for patients during and following cancer treatment.


.


Modulation of Immune Tolerance Through Active Substances


For the past 10 years, cancer researchers have been searching for adequate possibilities to influence IDO activity, thereby, controlling its disastrous effects. Physicians and patients urgently await active substances for clinical Phases I to III. One of the early substances, epacadostat, now is successfully evaluated for clinical phase III.

However, natural medicine also offers substances for the modulation of IDO. The aryl hydrocarbon receptor, shown in Figure 2 is important in the regulation of IDO activity as well as in the formation of kynurenine, and it can be inhibited with substances such as flavonoids, for example, curcumin, quercetin, or resveratrol. While environmental toxins such as dioxin activate IDO, the above-mentioned substances lead to a modulation of the AHR so that its regular signalling to IDO formation or activation is interrupted. Busbee et al. offer a review of effects of the molecular mechanisms of the natural substances on IDO activity (Busbee et al. 2013).


At this point we would like to give an example. The effect of curcumin on the activity of IDO in macrophages was clearly demonstrated by Jeong et al. (2008). IDO, induced by INF-gamma is blocked by curcumin in a dose-dependent manner (Jeong, et al. 2009).


.


Modulation of Immune Tolerance Through Sports


It has been known for a long time that moderate sports activity positively influences the immune system and the healing as well as self-healing energy, both before, and after illnesses. In 2015, the Karolinska Institute proved the decrease of stress-induced kynurenine levels through sports activity in a path breaking study. (Agudelo, et al. 2014) This realization can be used for the neurological side-effects such as fatigue induced by cancer treatment. It is known from the studies that (i) fatigue and elevated kynurenine levels are linked (Kurz, et al. 2012) but (ii) sports fatigue decreases its levels (Schuler, et al. 2016). The correlation of the level of kynurenine and sports activity closes the circle on the management of activity for patients with the goal to modulate IDO activity in favour of an optimal immune balance.​

 

[pattismith]

interesting to note that

-AH receptor inhibition by flavonoids or Curcuma produce less IDO activity
-Sport inhibits IDO

 

[Navid]

@HTester

 

[Belbyr]

interesting to note that

-AH receptor inhibition by flavonoids or Curcuma produce less IDO activity
-Sport inhibits IDO

Wonder what they mean by 'sport' or in other words, to what level? Golf or football?

 

[roller]

Wonder what they mean by 'sport' or in other words, to what level? Golf or football?

forced swim test ?

think they reference this one
Agudelo, L. Z. et al. (2014). Skeletal Muscle PGC-1•1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. Cell, 159(1), 33–45. http://doi.org/10.1016/j.cell.2014.07.051

 

[pattismith]

forced swim test ?

think they reference this one
Agudelo, L. Z. et al. (2014). Skeletal Muscle PGC-1•1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. Cell, 159(1), 33–45. http://doi.org/10.1016/j.cell.2014.07.051

This one may not be the forced swim test... well I hope not:

Schuler, M. K.et al. (2016). Impact of different exercise programs on severe fatigue in patients undergoing anticancer treatment – a randomized controlled trial. Journal of Pain and Symptom Management, http://doi.org/10.1016/j.jpainsymman.2016.08.01

 

[Wishful]

Their writing is unfortunately confusing. For example: 'IDO, induced by INF-gamma is blocked by curcumin in a dose-dependent manner ' made it unclear whether the production of IDO was blocked, or whether IDO's functions were blocked (it was the former). There were a few other similar confusing bits.

I find it interesting that : 'The aryl hydrocarbon receptor, shown in Figure 2 is important in the regulation of IDO activity as well as in the formation of kynurenine, and it can be inhibited with substances such as flavonoids, for example, curcumin, quercetin, or resveratrol.' Turmeric and resveratrol both strongly increase my ME symptoms. I'll take that as evidence that IDO is involved in my ME symptoms. What has me confused is that physical exertion, which induces IFN-g (and thus IDO?) approximately 24 hrs later, also increases my ME symptoms. This paper claims that the exertion reduces IDO production. I'm all confused now, and need to cogitate.

Thanks for the posting though. Maybe it will lead to some insight into ME.

 

[pattismith]

@Wishful

yes this Tryptophane pathway is really something that can be confusing,
so I summarized the paper by saying that both flavonoids and sport are IDO blockers.


What I understood from the metabolic try trap is that there is an IDO inhibition (specially in the brain, with too much serotonin in the brain). So in that case, if this metabolic trap is right, any IDO blockers may worsen ME, which means sport and flavonoids will make ME worse. (the sport is considered moderate in the paper).

 

[Wishful]

Yes, my problem at the moment is that I've spent 15 or more years believing that my symptoms were from too much IDO and the resulting nasty kynurenines. This new finding has shattered my model, and now I have to fit the pieces back into a new pattern.

It made sense that physical exertion and viral attacks produced the same response, through IFN-g and IDO, and that dietary tryptophan increased the symptoms. Now I need a new model that fits those observations and involves lowered IDO.

Oh, my poor shattered model.

 

[Wishful]

I haven't dug down into the full text of the paper that is supposed to show that sports reduces IDO (my brain is suffering from post-drive-to-town-sluggishness), but I am a bit suspicious of the claim and its application to ME. Has anyone already checked deep enough to confirm that 'sports (or muscle exertion) inhibits IDO production'?

I did come across another paper about KYN and IDO: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753541/

The part that caught my attention is: "However, proinflammatory cytokines upregulate the expression of IDO with inflammation status, resulting in the activation of another metabolic pathway of KYN. In this circumstance, KYN is more likely to be metabolized to quinolinic acid (QA), a neurotoxic metabolite [17, 18]. Moreover, activation of IDO shifts TRY metabolism from serotonin synthesis to KYN formation, inducing an imbalance of the serotonergic system [19]. This disorder of KYN pathway is hypothesized to underlie inflammation-associated depression and anxiety behaviors [20]."

The part about it shifting the KYN balance towards QUIN matches my observations. Some kynurenines make you feel good, while others make you feel bad. I had wondered whether ME could shift the balance towards the bad kynurenines.

 

[nandixon]

Turmeric and resveratrol both strongly increase my ME symptoms.

I've been having good success with thinking about everything in terms of Nancy Klimas's model for ME/CFS, which says that both the immune system and the HPA axis are simultaneity dysregulated and are in an unfortunately stable (i.e., homeostatic) relationship with respect to each other.

So in that regard, one finds that turmeric (active ingredient curcumin) and resveratrol both suppress the HPA axis, which is probably not what the majority of people with ME/CFS want. But then again both these substances have dozens of other major effects in the human body so it's impossible to say at this point.

(My experience with curcumin years ago, and verified multiple times, is that the first day or two of using it it's great, perhaps due to its anti-inflammatory (cytokine modulating) effect. Then I feel significantly worse thereafter. Resveratrol seemed more neutral but I may not have tried it at a high enough dose to gauge its true effects.)

 

[pattismith]

@nandixon

It seems that IDO2 can be inhibited by AhR inhibition.

Let's imagine that our IDO2 is inhibited (this is suggested by the metabolic try trap ).

Two studies here show that ArH inhibition leads to sex hormon disruption, and that plastic toxins are both inhibitors for ArH and androgen receptors!

I wonder if ME/CFS could be favored by plastic toxicity and if testosterone and AhR activators could be helpful.
(Testosterone has already shown efficiency in Fibromyalgia)


Disruption of Aryl Hydrocarbon Receptor (AhR) Induces Regression of the Seminal Vesicle in Aged Male Mice
Baba T.a · Shima Y.a · Owaki A.a · Mimura J.b · Oshima M.b · Fujii-Kuriyama Y.b, c · Morohashi K.-i.a, c

Accepted: January 02, 2008



Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates diverse dioxin toxicities. Despite mediating the adverse effects, the AhR gene is conserved among animal species, suggesting important physiological functions for AhR. In fact, a recent study revealed that AhR has an intrinsic function in female reproduction, though its role in male reproduction is largely unknown. In this study, we show age-dependent regression of the seminal vesicles, probably together with the coagulating gland, in AhR(–/–) male mice. Knockout mice had abnormal vaginal plugs, low sperm counts in the epididymis, and low fertility.

Moreover, serum testosterone concentrations and expression of steroidogenic 3βhydroxysteroiddehydrogenase (3βHsd) and steroidogenic acute regulatory protein (StAR) in testicular Leydig cells were decreased in AhR(–/–) males.

Taken together, our results suggest that impaired testosterone synthesis in aged mice induces regression of seminal vesicles and the coagulating glands. Such tissue disappearance likely resulted in abnormal vaginal plug formation, and eventually in low fertility.
Together with previous findings demonstrating AhR function in female reproduction, AhR has essential functions in animal reproduction in both sexes.

Plastic components affect the activation of the aryl hydrocarbon and the androgen receptor
TanjaKrügerManhaiLongEva C.Bonefeld-Jørgensen
.2007

Abstract
Phenols and plasticizers are widely used in the plastic industry, in food packaging and to impart softness and flexibility to normally rigid plastic medical devices and children's toys.
The effects on the aryl hydrocarbon receptor (AhR) and the androgen receptor (AR) were assessed using luciferase reporter gene assays of the following compounds: bisphenol A (BPA), 4-n-nonylphenol (nNP), 4-tert-octylphenol (tOP), bis(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP), diisodecyl phthalate (DIDP), di-n-octyl phthalate (DNOP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), 4-chloro-3-methylphenol (CMP), 2-phenylphenol (2-PP), 2,4-dichlorophenol (DCP), resorcinol and bis(2-ethylhexyl) adipate (DEHA).
Furthermore, a mixture of selected compounds was tested at the no-observed-effect concentration (NOEC), the low-observed-effect concentration (LOEC) and the half-maximum-effect/inhibitory concentration (EC50/IC50) of the single chemicals.

Both receptors were affected by BPA, nNP, BBP, CMP, DCP and resorcinol whereas DEHP, DIDP and DBP affected only the AhR and tOP and 2-PP antagonised the AR activity.

The mixture was composed of 6 compounds, of which one compound weakly induced the AhR but all compounds antagonized the AR activation. Using the concentration addition principle additive effects were observed at the NOEC, LOEC and EC50/IC50 for both receptors.

Our in vitro data suggest that the effect of a mixture depends on the concentration, character, potency and composition of the single mixture compounds and that also the combined effects of the compounds should be taken into consideration for risk assessment of human health.

 

[Wishful]

I couldn't find the paper claiming that sports inhibits IDO. However, I read (okay, skimmed) a paper ( https://www.cell.com/cell/fulltext/S0092-8674(14)01049-6 ) about sports modulating cerebral kynurenine levels. I think that's the basis of the claim that sports inhibits IDO. What it actually says is: 'Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier.'

It seems like they're talking about long-term endurance-type activity altering muscle cells in a way that they convert more KYN to KYNA, which means less KYN crossing the BBB and causing depression (and other effects such as might occur with ME). I found the following quote interesting:

'Approximately 60% of brain KYN comes from the periphery because, as opposed to KYNA, it can readily cross the blood-brain barrier (Fukui et al., 1991, Gál and Sherman, 1980).' However, I still think that TRP->KYN conversion by microglial cells is significant in my ME, since blocking TRP transport by BCAAs blocks the otherwise increase in symptoms. Maybe the peripheral KYN production causes the baseline symptom severity?

Also: ' In the brain, KYN is metabolized to KYNA by astrocytes and to 3HK in microglia and macrophages (Schwarcz et al., 2012).' KYNA is good. 3HK is nasty, as is its downstream product, QUIN. Another product, picolinic acid, increases TRH and thus TSH. I'm not sure if it also causes any of the unpleasant feelings associated with fevers.

I'm just guessing that the 'sports inhibits IDO' claim is also about long-term endurance activities and maybe small reductions in IDO. I don't take it as 'a short walk dramatically reduces IDO quickly'.

I'm sticking with ME involving elevated IDO in microglial cells. My model isn't shattered after all.

 

[ZeroGravitas]

I searched my way to this interesting thread after looking for more info on AhR (aryl hydrocarbon receptors). Which are proposed as a key part of the massively increased IDO2 expression and kynurenine production reportedly found in certain cells of PASC patients, in this new Dutch paper.

The authors there appear to think this positive feedback loop is at work (and can be broken with AhR antagonists).

However, it can also be induced via the so called aryl hydrocarbon receptor (AHR) through toxic substances (Busbee, et al. 2013) or in a positive feedback via products of the kynurenine pathway (Orabona & Pallotta, 2012).

(ii) Immune cells steadily form kynurenine which supports its own production through positive feedback.

But what I'm wondering is why all cells with IDO and AhR don't always just self trigger into this obviously pathological kynurenine feedback loop..?

 

[datadragon]

Sports/Exercise appears to have different effects on NLRP3 inflammasome (inflammation). In the case of chronic exercise with high intensity such as what occurs in many athletics/sports, a significant INCREASE in expression of gene, NLRP3 and serum levels of IL-1β, IL-18 cytokines were observed. Chronic exercise with light to moderate intensity such as walking however significantly reduced the expression of NLRP3 gene and subsequent serum levels of IL-1β, IL-18 cytokines. So there are differences in intensive vs light exercise with intensive pouring additional fuel on the fire of inflammation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524053/

NLRP3 inflammasome mediates the upregulation of IDO1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737528/ IFN-y is also induced by intense exercise, (and also strongly induces IDO1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/ and maybe PEM https://forums.phoenixrising.me/thr...nfa-itaconate-shunt-part-2.89388/post-2437712

Aryl hydrocarbon receptor (Ahr) negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription https://www.nature.com/articles/ncomms5738 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634667/

There are effects on orexin both from overexpression of serotonin which also appears to increase from inflammatory cytokines, and also going the other direction inducing IDO1 and therefore will shunt tryptophan away from serotonin. quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons from some notes I started here. https://forums.phoenixrising.me/thr...nfa-itaconate-shunt-part-2.89388/post-2438998

 

[datadragon]

The part about it shifting the KYN balance towards QUIN matches my observations. Some kynurenines make you feel good, while others make you feel bad. I had wondered whether ME could shift the balance towards the bad kynurenines.

tryptophan is metabolized to kynurenine via either indoleamine 2,3 dioxygenase (IDO1 or IDO2) or tryptophan 2,3 dioxygenase (TDO). Other than 3-hydroxykynurenine (HK), all subsequent metabolites require a vitamin B-6 (PLP)–dependent enzyme for generation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498264/ which is going to be less available under inflammation/immune conditions per some of the info from my other posts. such as the lowered uptake and unavailability of zinc for example. kynureninase (kynase) is a Vitamin B6 PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3-hydroxykynurenine (to produce 3-hydroxyanthranilate). This is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp). The other PLP-dependent enzyme of the KP, KAT, is also subject to inhibition in B6 deficiency or perhaps not getting utilized under inflammation as I am finding.

 

[Wishful]

quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons

The abrupt switching from full ME to full non-ME seems to rule out loss of slowly-reproducing cells. The abruptness and magnitude of the switch of state is what I consider indicative of a positive feedback loop. My mental model of ME's mechanism is a high-gain amplifier with multiple inputs, and inputs that vary the gain between negative to positive. Normally the gain is negative, but something shifts one or more inputs to make the gain positive, and the system snaps into one state and stays there. That could be something like IDO products feeding back to increase IDO production. It could involve more steps, maybe involving exosome production or glial process growth. The feedback loop could involve gut microbiome or lymph flow during sleep. It won't necessarily involve a dramatically abnormal level of a known factor; it could just be a combination of subtle variations from "normal", possibly all remaining within "normal" range, and they might be highly localized. Maybe serum kynurenine levels will be "normal", but the levels in the hypothalamus are 15% higher than they should be for that individual, and that's enough to push the gain of the feedback loop into positive gain, which causes some other factors to shift slightly that further increases the feedback, resulting in astrocytes doing some function 7% less well, resulting in the individual feeling totally crappy.

No orexin neurons need to die in that scenario.