Welcome back from your intermission! It’s now time to begin act two of our inflammatory-cortisol ballet.

In the first act we saw what happens when cortisol is low, as in adrenal insufficiency, and what occurs when cortisol is high, as in Cushing’s syndrome.

But it’s now time to introduce the other members of our inflammatory-cortisol ballet. At the risk of mixing my metaphors, it takes two to tango. And in the case of our ballet, the other partner in this dance is the immune system, specifically immune cells and their inflammatory cytokines.

Immune Cells and Cytokines

Broadly speaking, cytokines are small proteins secreted by a variety of cells that affect the behavior of other cells. When we’re talking specifically about the immune system, we’re mainly talking about how these proteins coordinate an immune response when a pathogen or pathogens are detected.

There are different types of cytokines released by many types of immune cells, and there is no possible way I could do justice to this subject in a blog post. The immune system is extremely complex and can easily consume a lifetime in study.

Therefore, I’ll be concentrating on one cell type above all others. He certainly isn’t the only hoofer in this ballet, but he does have a starring role. And that dancer was briefly introduced to you in the first act as the macrophage cell, he of the very big appetite.

Macrophage cells are part of our innate immune system, although they also take part in adaptive immunity. The innate immune response is that part of the immune system that serves as our first line of defense. Well, it’s our first line of defense if we disregard both our visible skin and our internal skin i.e., the skin cells that line our respiratory system and gastrointestinal tract.

Macrophage cells are also known as sentinel cells, and they’re called that because they reside under the surface of the skin, lungs, sinuses, oral cavity, stomach and intestines—in other words areas next to the outside world, which if breached by pathogens can present a threat to our health and very survival.

All macrophages can exist in three different states of readiness. The lowest state of readiness is the resting state.

In this state, macrophages sample the area around them sniffing, as it were, for any trouble. They also eat or phagocytose cellular debris.

Every second of our lives, about one million cells die. That means that 60 million cells die every minute or a bit over 3 billion cells an hour. That’s a lot of cellular debris the body needs to clean up to keep things nice and tidy. And that cleanup is done by macrophages that act not only as sentinels but as glorified garbage collectors.

How do they know which cells should be eaten and which ones left alone? Well, cells that have reached the end of their lives send out signals that attract these garbage collectors. When close, macrophages are able to read “devour me” signs displayed on the surface of these dying cells, and that’s precisely what macrophages proceed to do.

Macrophage cells are pretty long-lived as far as immune cells go. They can easily live for months and spend a good chunk of their time lazily eating our cellular trash.

However, macrophages not at rest come in two types. Type one is a killing machine and described below. Type two macrophages aid in wound healing, and tissue and muscle repair. These macrophages help end the inflammatory process initiated by the first type.

When pathogens of any type breach the gut wall, a normal occurrence in gut dysbiosis, so-called naive macrophage cells receive a signal that something’s not right. They become activated as type one inflammatory macrophages. In this state, they start taking bigger gulps of their surrounding environment.

This activation typically occurs in response to a cytokine known as interferon gamma (INF-y). This cytokine is mainly produced by helper T cells and natural killer cells. INF-y not only activates type one macrophage cells, it can also cause these same cells to produce other cytokines that make both T cells and natural killer cells continue to release INF-y to keep the inflammatory cascade going.

But there is another state where type one macrophages become hyperactivated. This state is entered when these cells directly encounter an invader. Remember our old friend lipopolysaccharide (LPS), the outer cell wall component of gram-negative bacteria? Macrophages can bind LPSs on their cell walls, as well as mannose, a common carbohydrate component of other pathogens like Candida albicans, viruses like the flu or HIV, gram-positive bacteria and parasites.

When hyperactivated, these formerly chill garbage collectors are turned into mean killing machines. They become larger, and their appetite really grows as they chomp on invaders left and right.

In this state they produce a very powerful cytokine by the name of tumor necrosis factor alpha (TNF-α). This cytokine is so named because it can kill tumor cells and cells infected by viruses. This cytokine can also cause other immune cells to release substances that kill pathogens and infected cells.

Furthermore, macrophages can produce other cytokines like interleukin 1 (IL-1) and interleukin 6 (IL-6). It is therefore very common to find IL-1, IL-6 and TNF-α present together during an immune threat.

Inside of these large, eating killing machines, reactive oxygen species like superoxide anion and hydrogen peroxide are produced. As many of you know, hydrogen peroxide is a very powerful anti-bacterial agent. Also produced are reactive nitrogen species like nitric oxide and peroxynitrite–all toxic to bacteria.

When macrophages are overwhelmed by an attack, they send signals for another type of immune cell to join the battle: neutrophils. These cells circulate in blood and are attracted to the site of an infection.

Neutrophils are professional killers once activated. Because of that, you don’t want too many of these hanging around for prolonged periods, or you risk some serious damage to surrounding tissue and organs.

In fact, the substances emitted by neutrophils, including TNF-α and IL-1, can literally liquefy both cells and connective tissue. For that reason, these cells have a life of only about five days, after which they are programmed to commit suicide.

I want to briefly highlight some of the different types of inflammatory cytokines that are secreted by activated macrophage cells:


Courtesy: Kuby Immunology, 7th Edition

Courtesy: Kuby Immunology, 7th Edition


Note that all but one of these cytokines are secreted by activated macrophages. On the right, we can read what tissues and other parts of the immune system these cytokines affect. NK stands for natural killer cells, and MHC stands for major histocompatibility complex. MHC proteins act like billboards alerting immune cells to what is going on inside an infected cell.

Cytokines often overlap in the effects they have on cells and tissues, so there is a bit of redundancy built into the system. Note that IL-1 and TNF-α both act on the vasculature, causing inflammation.

While it would be incorrect to treat these cytokines as interchangeable, we can say they share some commonalities as seen in the following chart:


Courtesy: Ruby Immunology, 7th Edition

Courtesy: Ruby Immunology, 7th Edition


Plus signs show that the cytokine in question has an effect, where a negative sign shows the opposite. I won’t be detailing what these effects are, but wanted to show you that many of these actions overlap.

I want to focus on TNF-α because it is a very powerful pro-inflammatory cytokine that is always produced when bacteria, especially gram-negative bacteria, breaches the gut wall. This cytokine derives its name from an observation made by a surgeon called William Coley at the turn of the 20th century.

What Dr. Coley observed was that when some of his cancer patients developed a certain type of bacterial infection, their tumors would begin to die. In the belief that he might have stumbled upon a cure for cancer, he began injecting what were called “Coley’s toxins” into patients. While it did induce tumor death, there were a significant number of side effects making his cure highly unsuitable.

And the reason why was because “Coley’s toxins” were what we now call lipopolysaccharides. However, it wasn’t the LPSs that had this effect, but the release of TNF-α.

Interesting as this story is, the name tumor necrosis factor didn’t come into use until much later. This cytokine was originally named cachexin. Why? Because it caused cachexia when secreted in large amounts.

Cachexia is a wasting away of the body due to illness, and TNF-α appears to be the proximate cause of this debilitating condition. This discovery was first made when infected rabbits were observed to lose half their body weight after a two-month infection.

Both TNF-α and IL-1 reduce the desire to eat, so both are classified as anorexic cytokines. They also ramp up metabolic rate, both as a consequence of fueling the energy requirements of an activated immune system, and as a result of inducing increases in body temperature to fuel fever.

Note that both actions are opposite to what cortisol does, namely increase appetite and slow metabolic rate. In fact, many of the actions of TNF-α oppose those of cortisol and vice versa.

Where chronic cortisol release raises blood pressure, inflammatory cytokines if unchecked can cause life-threatening drops in blood pressure. Cortisol increases blood glucose levels, while TNF-α can lead to very low blood-glucose. Cortisol excess causes elevations in LDL cholesterol, TNF-α causes a decrease in the same. (1) But while LDL levels decrease, the LDL particles that are left tend to be of the small, dense variety, which are atherogenic.

One area where TNF-α and cortisol seem to have synergistic effects is in the genetic expression of adipose or fat tissue. Both promote pathways that cause adipose cells to differentiate into a type that causes the body to accumulates fat as visceral fat, and not as less metabolically active subcutaneous fat.

Both also cause fat breakdown. However, in those with either elevated serum and/or cellular cortisol levels, this fat breakdown is overcompensated for by stimulation of eating behavior that results in overall weight gain.

In situations where TNF-α is not adequately opposed by endogenous cortisol secretion or metabolism, the anorexic effect of this cytokine, along with IL-1, leads to an overall decrease in appetite. When coupled with the overall catabolic actions of both TNF-α and whatever cortisol is being released, a condition akin to anorexia nervosa is typically observed.

Anyone intimately familiar with the immune system knows I’ve simplified things a bit. However, my purpose is to get you to understand how wide-ranging these immune reactions are in response to invading pathogens, including those caused by increased intestinal permeability.

Now the immune system has a number of mechanisms to make sure these reactions are self-limiting to prevent damage to healthy cells and tissue. For example, the type 2 macrophages I spoke of earlier are involved in ending these inflammatory cascades and promoting healing.

Unfortunately, as in the case of autoimmune disorders, these mechanisms don’t always work. Once again, for the sake of brevity and my sanity, detailing what those immune mechanisms are is far beyond the scope of this post.

But as I’ve already hinted, these anti-inflammatory mechanisms are not strictly limited to the immune system. The hormonal system is also involved in keeping a lid on these processes, with cortisol as the primary counterweight to uncontrolled immune activation.

Remember the anti-inflammatory (immune-suppressing) role cortisol plays, which is a major reason drug companies developed synthetic corticosteroid drugs in the first place? Well, inflammatory immune activation always calls forth compensatory anti-inflammatory responses that lead to an increase in cortisol secretion, and its conversion from inactive forms to active ones.

It appears counter-intuitive that the body increases the secretion and metabolism of an anti-inflammatory substance like cortisol (which can potentially lead to all the side effects I covered in the first act) at the same time its own immune system is busy creating inflammation to kill invading pathogens. Why would the body take back with the right hand what it gives with the left?

Because runaway inflammation can kill you. Any ICU doctor or nurse can tell you that. In the case of bacterial sepsis, for example, it’s not the infection that kills the patient, it’s the runaway immune response—inflammatory cytokines, reactive oxygen species, reactive nitrogen species—that can cause severe tissue damage and organ failure.

In fact, sepsis patients who for whatever reason are least able to produce cortisol in response to acute immune activation are also less likely to survive this life-threatening condition. (2) Known as critical illness-related corticosteroid insufficiency, this inability of the body to tamp down a runaway immune response contributes to the high mortality rate in this group of patients.

In the first act I wrote:

“To use a metaphor, cortisol is an active dance partner of inflammation and the cytokines that drive immune responses. It often moves left when inflammation moves right, back when the other moves front–like Swan Lake, but with more Sturm und Drang.”

And indeed, that’s precisely what cortisol does. The ‘yin’ to inflammation’s ‘yang’, cortisol, like so much else in the body, has more than one role to play. While it clearly can cause us problems when in excess, it also protects us from an immune system that if left unchecked, can run amok and kill us.

In a nutshell, when there is immune activation, cortisol is dancing right along with it to keep things under control. To further flesh out my metaphor, cortisol is the Margot Fonteyn to inflammation’s Rudolf Nureyev.

There can be no gut dysbiosis without immune activation. And there can be no immune activation without compensatory cortisol release and/or metabolism.

Imbalances can occur between inflammatory immune responses and the anti-inflammatory actions of cortisol. I’ve already hinted at two instances in those exhibiting anorexia and those septic patients who fail to pull through their infections. I’ll have more to say about this in the next act. (What? You didn’t really think this ballet would only be two acts long did you? It is a ballet after all. Don’t be so uncouth!)

In addition, I’ll briefly explain how cortisol is regulated, and how inflammatory-immune responses call forth cortisol secretion from the shadowy depths of the adrenals. And within cells, we’ll see how our inflammatory Nureyev, with the aid of a danseur poetically named 11β-hydroxysteroid dehydrogenase type 1, amplifies the many arabesques and pirouettes of our star ballerina, Margot ‘Cortisol’ Fonteyn.



Owen, J. A., Punt, J., Strandford, S. A., & Jones, P. P. (2013). Kuby Immunology (7th ed.). New York: W.H. Freeman and Company.

Sompayrac, L. (2012). How the Immune System Works (4th ed.). Malaysia: John Wiley & Sons.

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