Part 2 of 3

In the previous blog, I introduced RANTES and how it is associated with inflammation. What had sparked my interest is that I have had a lot of patients come to me with a very unique presentation of inflammation revisited induced after COVID-19. I this previous blog, I discussed RANTES, TNF-a, NFK-B and nitric oxide.  I explained why this type of induced inflammation revisited can be such a problem for many common chronic conditions I see in clinical practice. I also explained what can stimulate RANTES. 

In this current blog, I want to dive a bit deeper into platelets, IL-6, mast cells and histamines, oxalates and inflammation revisited.

So, if you recall, I mentioned that platelets can stimulate RANTES.  This interaction is bidirectional as the activated cells can activate platelets through a number of receptor-ligand systems.  The strength of RANTES depends on the preexistence of NFK-B. 

Also, TNFA-a stimulates NFKB as does iron (as seen in chronic Lyme- they seem have 8x higher HFE genes that cause them to absorb more iron). Iron serves as a direct agonist to activate NFKB, and TNF-a promoter activity to induce the release of TNF-a protein. 

Histamine also enhances RANTES. Mycotoxins or sources of LPS cam stimulate TNF-a and begin a cascade of inflammation revisited leading to RANTES.  Whoa! I also discussed things that can stimulate NFK-B in this blog as well.

TNF-a is a pro-inflammatory cytokine that is stimulated by the presence of pathogens during an infection.  It is not evil; in fact, it can be helpful during an infection. It can stimulate NFK-B which then stimulates NADPH-oxidase to stimulate Interleukin-6, which then stimulates NOX. 

IL-6 pathway/upregulation

Interleukins are a class of endogenous chemical mediators involved signaling between cells, particularly white blood cells (leukocytes).

inter – between Leuk – reference to leukocytes

Interleukins are a type of cytokine. The term “cytokine” is derived from a combination of two Greek words – “cyto” meaning cell and “kinos” meaning movement.

Cytokines are cell signaling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation revisited, infection and trauma.

There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and peripheral inflammatory responses.

Inflammation cytokines secretion by immune cells


IL-6 is critical for immune defenses. Our immune system and white blood cells are critical for protection against pathogens, and development of infections. IL-6 is an essential messenger within the immune system. Acute inflammation revisited signals for tissue repair, and inflammatory responses designed to initiate healing, or protection against invaders.

On the other hand, unresolved chronic inflammation has been associated with many health concerns.

Total elimination of IL-6 in animals has shown to increase susceptibility to various infections.

IL-6 is also a beast.

It can be simulated for a variety of reasons.

These include:

  • Genetic polymorphisms on IL-6
  • Environmental factors- mold, Lyme, EMF, LPS, air pollution, smoking, stress, metals, glyphosate, Omega 6, pesticides, MTOR
  • Long-term exposure to EMFs probably affects immune responses, by stimulating the production of proinflammatory cytokines”. EMF Stimulates Calcium and superoxide. Superoxide stimulates PLA2

IL-6 can stimulate:

  • mast cells
  • superoxide
  • histamine

C-reactive protein (CRP) is a major mediator of acute phase inflammation, and is often measured to evaluate underlying levels of inflammation revisited. Elevated CRP is often considered a potential sign of chronic inflammation– Specifically, IL-6 is a major regulator of CRP expression (transcription), and appears to be essential for induction.

When comparing successfully aging individuals to those with aging-related diseases/disability there was lower IL-6 levels in the successfully aging group. Longer survival was associated with lower concentrations of IL-6 and CRP.

COVID and IL-6

During a meta-analysis and systematic review, elevated IL-6 levels were found to be significantly associated with adverse clinical outcome.  For example, there was a reported 2.9- fold increase in mean IL-6 concentrations in complicated COVID-19 cases

Evidence shows that pro-inflammatory cytokines play a pivotal role in the pathophysiology of lung damage in patients affected by coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2).

A lot of patients affected by SarsCoV2 develop a damaging immune reaction sustained by cytokines leading to alveolar infiltration by macrophages and monocytes.  Interleukin-6 (IL-6) is one of the main mediators of inflammatory and immune response initiated by infection or injury and increased levels of IL-6 are found in more than one half of patients with SarsCOV-2.

Levels of IL-6 seem to be associated with inflammation, respiratory failure, needing for mechanical ventilation and/or intubation and mortality in COVID-19 patients.

IL-6 & Endogenous Mediators

Below is a list of a few things that can induce IL-6 endogenously.

  • Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with impaired glucose tolerance.
  • Adipose tissue is one of the main sources of inflammatory mediators, including interleukin-6 (IL-6). In human aortic endothelial cells, IL-6 was found to increase NOX2 activity in a concentration and time-dependent mechanism
  • Angiotensin II administration was found to induce IL-6, and subsequently NOX and VEGF
  • OXALATES stimulate IL-6 production in renal epithelial cells
  • Elevated homocysteine increases IL-6 production
  • Ochratoxin A, a mycotoxin from mold, significantly increased IL-6 and may promote inflammation revisisted in the nasal epithelial cells.
  • Published studies report these Mycotoxins are the strongest drivers of IL-6 secretion: Verrucarin, Ochratoxin A, Sterigmatocystin
  • Lipopolysaccharides from Gram Negative Bacteria induces tumor necrosis factor and IL-6

HOLMES cycle

Superoxide, mast cells, and histamine stimulate renin-angiotensin system, which makes more IL-6 in a feedback loop, but also makes angiotensin II that stimulates RANTES.

Toxic environmental factors and genetic predispositions cause overstimulation of NOX (NAPH oxidase) which results in overproduction of superoxide, peroxynitrite, mast cells, histamine and glutamate.

The NOX enzyme uses NADPH to produce the free radicals, resulting in what has been termed the NADPH steal, resulting in less ability to have sufficient NADPH to support Phase 1 detox, produce NO and recycle critical antioxidants such as glutathione. 

In turn, free radicals produced by NOX stimulate renin, angiotensin I, angiotensin II, aldosterone, IL-6 and NOX, resulting in a positive feedback loop that creates a self-perpetuating viscous cycle of inflammation revisited named the Holmes cycle.

Remember…histamine makes more RANTES.

Mast cells are a unique source of renin- as you make mast cells, it will stimulate renin.

Histamine has been shown to stimulate the release of renin as well.

Superoxide increases renin.

Angiotensin II can activate NADPH oxidase within the cardiovascular system to generate reactive oxygen species (ROS) and hydrogen peroxide.  However, ROS can also act upstream to the renin-angiotensin-aldosterone-system (RAAS) and increase activation.


I have talked about this in many of my lectures and podcasts. Oxalates are nasty and very pro-inflammatory. OXALATES stimulate IL-6 production in renal epithelial cells. 

If you have followed me for quite some time, you know I talk a lot about oxalates in the diet and toxic superfoods.

I also discuss endogenous oxalate production via various biochemical pathways.

I also discuss mold toxicity, fungal overgrowth and oxalates.

Well, there are also some genetics behind it too.

The HOGA1 gene encodes mitochondrial 4- hydroxyl-2-oxoglutarate aldolase, which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. The HOGA1 gene is predominantly expressed in the liver and kidneys. Variations in the gene may lead to hyperoxaluria type 3. Hyperoxaluria type 3 is caused by the overproduction of oxalates.

The protein encoded by SPP1 is involved in the attachment of osteoclasts to the mineralized bone matrix. Studies have shown that the GG genotype for rs2853744 increases the likelihood for calcium oxalate urolithiasis.  I have this mutation, and am heterozygous for it.

The GRHPR provides instructions for making the enzymes glyoxylate, and hydroxypyruvate reductase. This enzyme plays a role in preventing the buildup glyoxylate by converting it into glycolate. Variations in this gene can cause a reduction in the conversion of glyoxylate to glycolate. Glyoxylate builds up and is converted to a compound called oxalate. Oxidative stress can also upregulate this process too. 

The AGXT gene provides the instructions for making an enzyme called alanine-glyoxylate aminotransferase. Alanine-glyoxylate aminotransferase is found only in liver cells, specifically within peroxisomes. Peroxisomes are important for removing toxic substances from the cells and helping to break down certain fats. In the peroxisome, alanine-glyoxylate aminotransferase converts glyoxylate to glycine. Variations in this gene may lead to type I primary hyperoxaluria.

Many nutrients are also involved in these pathways. These include B1, B2 and B6.

But…I digress….


One of the hallmarks of hyperoxaluria is also mast cell activation.  This condition (MCAS) is likely present in at least 9-14% of the population, but it is likely growing.  NOX can stimulate mast cells to promote histamine.

Below is an image that summarize some of the inflammatory mediators involved with mast cell activation. Patients with MCAS are some of the sickest I have ever worked with.  Mast cells can be promoted by infections such as Lyme, Bartonella and Mold toxicity.  MCAS describes a dysregulation of mast cell activity, or misbehaving mast cells. Overstimulated and uncontrolled.

Mast cells and inflammation revisited

Mast cells create histamine, and your genetics can influence this too!

  1. You need cortisol to knock out histamine
  2. There is a mutation/ SNP CYP21A2 is involved in converting progesterone to cortisol, inhibiting it
  3. ABP1- makes DAO to break down histamine. ABP1 encodes for the copper-containing DAO enzyme that degrades Histamine, but it also clears histamine with the DAO enzyme. (DAO supplementation can often be helpful)
  4. HMNT- need SAMe that degrades histamine
  5. MAOA- used to clear histamine- and SIRT 1 supports it and this also uses FAD. More on SIRT 1 later. MAO-A and MAOB are involved in degrading Dopamine (and removing histamine)/Riboflavin (B2) is a co-factor for MAO-A. Check Riboflavin enzymes and supplement if needed
  6. UGT1A4- another pathway that clears histamine through glucuronidation. HDC (histidine decarboxylase) also uses B6 as a cofactor to convert amino acid histidine to histamine. Iodine, testosterone and ECGC inhibit this. This enzyme is why many people cannot tolerate vitamin B6, but I suspect if you improved your iodine levels or balanced hormones, you may be able to downregulate this pathway. Iodine, Testosterone and ECGC calms HDC

If there are many SNPs, and low methyl groups (poor methylation and SAMe) there is the potential for high histamine.

Quercetin and Nettle Leaf may be helpful…but you really need to get to the source of the problem to resolve your histamine issues. Mold toxicity is often a big culprit.

Histamine can stimulate iNOS

Histamine (no matter the source) stimulates intimal smooth muscle cells to increase iNOS expression via H1 receptors and NF-kB signaling pathway. So, the symptoms can also be due to iNOS upregulation.

Superoxide dismutase (SOD) neutralizes superoxide and SIRT1 helps, but you can have mutations on both SOD and SIRT1.  And inflammation feeds this cycle, called NOS uncoupling.

 Side note- depletion in BH4 (tetrahydrobiopterin) can worsen this presentation.

**If BH4 is depleted, you will run on BH2.  If BH4 is depleted and run off BH2, rather than making NO, we make superoxide, that then combines with NO to make peroxynitrite, and further suppresses BH4 and iNOS suppresses eNOS.

BH4 is the cofactor for tyrosine to L-DOPA- and sometimes if people take tyrosine and it doesn’t work, its BH4 deficiency. You also need BH4 to convert tryptophan to serotonin, and phenylalanine to tyrosine.  That is why some do terrible on aspartame, they don’t have BH4.

Royal Jelly is a natural source of BH4

Many genetic factors affect BH4 production, starting with Succinyl CoA in Kreb’s and also MTHFR.

Methylation and inflammation revisited

Remember, other things can also stimulate iNOS. 

  • Aluminum
  • Mercury
  • Uranium
  • BPA
  • Ethanol
  • EMF
  • HFCS
  • Gluten
  • Chlorine
  • Fluoride
  • Glyphosate
  • Homocysteine
  • iron overload
  • Mold
  • LPS (clostridia)
  • pesticides

Genetic mutations can stimulate iNOS. Gain of function mutations in NOS2 (iNOS) enzymes, mutations in other enzymes over stimulating iNOS along with environmental and endogenous stimulation of NOS2 (iNOS). I talked about this a bit in the first blog.


Beyond hemostasis and thrombosis, an increasing number of studies indicate that platelets play an integral role in intercellular communication, mediating inflammatory and immunomodulatory activities.

The basic function of platelets is rapidly binding to damaged blood vessels, aggregates to form thrombi, and prevents excessive bleeding. However, activated platelets also aggregate at the site of atherosclerotic plaque rupture or endothelial cell erosion, stimulating thrombus formation and promoting atherothrombotic disease.

Activated platelets also express CD40L. Recent work has revealed an essential involvement of soluble CD40L (sCD40L) in inflammation and vascular disease- which can increase VEGF, tumors and MDSC (myeloid derived suppressor cells)- the higher the MDSC, the worse the outcome.  It is important that SCD40L does not get carried away.

Vascular endothelial growth factor (VEGF) is a potent and specific angiogenic factor.

In addition to playing a central role in normal hemostasis and thrombosis, platelets can make important contributions to host inflammatory and immune responses to infection or injury. Under uncontrolled pathological conditions, they have profound roles in pathogenic processes underlying atherosclerosis and cardiovascular diseases, uncontrolled inflammation, tumor metastasis, and neurodegenerative diseases including Alzheimer’s disease

Olive Oil contributes to vascular homeostasis by inducing PGI2 release in a Cox-2- dependent manner.  It will shunt AA to prostacyclin which inhibits platelet activation and is vasodilative. 


The COMT is involved in breaking down excitatory neurotransmitters, including Dopamine and detox reactions.

Tyramine foods, Estrogen and Quercetin downregulates COMT while testosterone upregulates. 

Since COMT is SAMe dependent, adequate SAMe (methylation) is needed for adequate COMT activity.

Caution with Quercetin and Tyramine foods when you have these mutations. MAO-A and MAOB are involved in degrading Dopamine (and removing histamine)/Riboflavin (B2) is a co-factor for MAO-A. Check Riboflavin enzymes and supplement if needed.

Dopamine beta hydroxylase is the enzyme that supports Dopamine to Nor-epinephrine conversion Potential interventions, 5-HTP, Copper, Fumaric Acid, Magnesium Taurinate, SAM-e

Omega 3’s Resolvins and Protectins

Some people know too well that it is important to eat fatty fish or supplement with fish oil to control inflammation. In fact, omega-3 supplementation is associated with a significant reduction in platelet aggregation.

Both EPA and DHA get incorporated into platelet phospholipids at the expense of arachidonic acid (AA), which may help reduce platelet aggregation via a reduction in AA-derived platelet-aggregating/procoagulant metabolites. EPA competes with AA for cyclo-oxygenase reducing its action on AA.

EPA/DHA also gets incorporated into neutrophils and red blood cells at the expense of both linolenic acid and arachidonic acid. The incorporation of omega-3s in red blood cells seems to decrease whole blood viscosity and increase red blood cell flexibility thus likely reducing the risk of thrombosis

The discovery of resolvins and protectins is of particular significance, since these potent lipid mediators provided the first molecular basis for the many health benefits attributed to the omega-3 fatty acids EPA and DHA, which are abundant in fish and are widely used as dietary supplements

Both EPA and DHA get incorporated into platelet phospholipids at the expense of arachidonic acid which may help reduce platelet aggregation via a reduction in AA-derived platelet aggregating/procoagulant metabolites.

When you have acute inflammation, you can either go into chronic inflammation via prostaglandins and leukotrienes, or you can have complete resolution with lipoxins, resolvins and protection

Therefore, arachadonic acid can be involved with either inflammation or resolution, but EPA and DHA is all involved with resolution.

Mutations in FAD1

Human genetic variants near the FADS (fatty acid desaturase) gene cluster (FADS1-2-3) are strongly associated with cardiometabolic traits including dyslipidemia, fatty liver, type 2 diabetes mellitus, and coronary artery disease

FADS1 as an underappreciated regulator of inflammation initiation and resolution, and suggest that endogenously synthesized arachidonic acid and eicosatetraenoic acid are key determinates of inflammatory disease progression

Loss of FADS1 activity promoted hepatic inflammation and atherosclerosis.

So there you have it, the science behind various pathways of why you are inflamed. This includes genetics, environmental and nutritional. In part 3, I will dive a bit deeper on various interventions that can help reverse this mess to help you improve your symptoms.