Can inflammation actually be good or is it just all bad?
The reason for this question is that a certain (actually quite famous) inflammatory cytokine, interleukin 6 (IL-6), has been reported to have beneficial effects.
Those benefits are touted as promoting hypertrophy and enhancing fat loss and blocking the effect of IL-6 inhibits that fat loss benefit. But is it a good idea to boost it?
Before we jump on the IL-6 boosting train, let me just say that it’s only the IL-6 that’s released from skeletal muscles during exercise that’s thought to be good. The IL-6 released from adipose tissue (the more fat you have the more inflammation you produce and the more issues it creates), monocytes, fibroblasts, vascular endothelial cells, etc., are mainly negative. This excludes the acute release of IL-6 from immune cells to kill viruses and bacteria.
Some “benefits” of IL-6 include:
- Activating the proliferation of cells in skeletal muscles, including satellite cells. Animals with IL-6 knockout (that don’t produce IL-6), have blunted accretion of myonuclei, while protein synthesis pathways are preserved. This impaired myonuclei incorporation is a consequence of the defective proliferation and migration capacities of satellite cells in the absence of IL‐6. Importantly, a complementary role to IL‐6 in stimulating muscle growth may be attributed to IL‐4 (which is anti-inflammatory as opposed to IL-6) because it promotes myoblast fusion without affecting their proliferative capacity. Similar to IL‐6, IL‐4 is produced by exercising muscle.
- Increasing GLUT4 and glucose uptake in muscles, but when increased chronically can degrade the insulin receptor and induce insulin resistance. IL-6 mRNA expression correlates negatively with insulin sensitivity and positively with liver lipid accumulation, due to elevated lipolysis from visceral fat (R).
- Increasing lipolysis as well as fat oxidation and this effect is mostly in the muscles and visceral fat and not so much other fat stores. So yeah, it doesn’t really promote fat loss. Busted.
- Increasing glucose production in the liver when glycogen runs low.
- Increasing insulin secretion.
- “Anti-inflammatory” in the sense that it increases IL-1ra (IL-1 receptor antagonist), IL-10 (anti-inflammatory cytokine) and cortisol (which is anti-inflammatory, but also catabolic) and decreases TNFα without concomitant increasing other pro-inflammatory
- Stimulating GABA release (but can also cause GABA dsyfunction) and GABA in turn reduces IL-6 again (R).
- Increasing dopamine production, but causes neuro-inflammation and loss of dopamine neurons in the long term (R).
Some negatives of IL-6 include:
- Promoting inflammation
- Increasing cortisol
- Inhibiting thyroid hormone conversion
- Decreasing circulating amino acids, thus reducing muscle turnover, because the amino acids are used for gluconeogenesis.
- Promoting muscle wasting in fast twitch muscles mostly. IL-6 increases muscle breakdown, reduces muscle turnover and uses those amino acids released from the muscle to create glucose.
- Reducing IGF-1 levels, because of reduced IGFBP-3 production. Reduced circulating IGFBP3 is associated with increased proteolysis, because low IGFBP-3 increases IGF-1 clearance from the body.
What increases IL-6?
- Hot environment
- Elevated intracellular calcium. This can be due to too much acetylcholine, nitric oxide, estrogen, magnesium deficiency, etc.
- Low blood sugar
- Adrenaline (R). However this effect is very mild. A 24 fold increase in adrenaline caused only a two- to threefold increase in IL-6 (R).
- Angiotensin II
- Polyunsaturated fat
- Low glycogen stores
- Oxidative stress
- Sleep deprivation
- Niacin, which blocks lipolysis, lowers IL-6, but causes a great rebound after a few hours and this significantly increases IL-6.
- Exercise, if done to, or close to, exhaustion.
- Low DHEA. The age-related increase in circulating IL-6 levels in humans which has been attributed to a decline in DHEA production by the adrenal gland (R).
- Dopamine. Dopamine D2 receptor stimulation increases IL-6 and leptin in adipose tissue, which can actually help with fat loss (R). This can actually be seen as a good thing and the dopamine boosted IL-6 is small and not pathological. Dopamine also promote physical activity and energy expenditure.
Exercise only mildly increases IL-6 compared to other insults, like bacteria, endotoxins, viruses, etc, but it does so in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise.
Intense exercise, such as lifting heavy weights or doing a full out short distance sprint, will not increase IL-6 all that much, whereas lifting weights for longer than 1 hour or doing long duration cardio will increase IL-6 to a much greater degree.
This is mostly because IL-6 is actually an energy sensing molecule and not so much a hypertrophy promoting substance, else cardio doing folks would be much more muscular due to a greater rise in IL-6.
As glycogen stores start to run low, IL-6 increases glucose uptake into muscles (this will boost recovery) and increases intramyocellular lipolysis and fat oxidation. This is totally normal because if one fuel source runs out, your muscles have to use another source.
So the more exhaustive the exercise becomes, the higher IL-6 rises. When exercise is done for less than 6 minutes, IL-6 increases only 2 fold. When exercise duration is kept just below 1 hour, IL-6 increases 10 fold. As the duration increases, so does IL-6 levels. In extreme cases such as a 246 km “Spartathlon” race, IL-6 can increase 8000 fold, but in more “normal” situations such as with running semi to full marathons, IL-6 can increase by 100-fold.
Interestingly, IL-6 does not increase as a result of muscle damage, as there is no difference in IL-6 levels between cycling (concentric only) or eccentric only training, but there is a double increase from running (R). This just shows that running is a pretty stressful type of cardio to begin with.
People who don’t exercise might have higher IL-6 levels at rest and proper exercise can help to lower resting IL-6 levels. There’s also evidence that shows that only beginners get a large increase in IL-6 (76 fold) from exercising. However, this response is decreased over time and after 10 weeks it’s only an 8 fold increase. The IL-6 clearance rate is also greatly increased with training status which results in a much faster decline in IL-6 level post-training.
Men with more training experience will have an even lower IL-6 response, but the harder you train the greater the IL-6 response will be. To “compensate” for this reduction in IL-6 levels in response to training, the body increases IL-6 receptors in the muscles, so it’s a net positive at the end of the day, as your muscles will still benefit from IL-6 and you’ll have low IL-6 levels at rest (R).
Chronically elevated IL-6, even at lowish levels, is not a good thing. Although it might not cause muscle wasting at low levels, it still negatively influences general health and is negatively correlated with exercise performance and strength (R). So the more strenuous you train, the more IL-6 you create and the more your subsequent exercise performance will suffer if your body doesn’t lower it rapidly enough afterwards, and you don’t recover enough between sessions. More overweight/obese individuals should be even more careful of training, especially long duration cardio, as the inflammatory response to training is so much greater than in lean individuals. And as a result, this will contribute to an overall negative systemic effect and deterioration of health.
Furthermore, elevated IL-6 is shown to be involved in age-related diseases, such as atherosclerosis, dementia, type 2 diabetes, osteoporosis, inflamm-aging, sarcopenia (cachexia or muscle wasting), muscle weakness, colon cancer, kidney damage (IL-6 is actually a very accurate measure (88%) for kidney damage and early kidney failure) (R), anemia (R), rheumatoid arthritis, Castleman’s disease and systemic juvenile idiopathic arthritis and other autoimmune diseases, etc.
The small increase in IL-6 caused by short intense exercise doesn’t correlate with muscle damage, but chronic long duration cardio, which causes an elevation in IL-6 and cortisol, will lead to muscle loss over time.
After proper exercise, IL-6 is rapidly cleared by the liver and kidney, with a half life of between 5 to 11 minutes. Improper exercise and nutrition can cause IL-6 to be elevated 2 days post-exercise and even more depending on training-, anti-oxidant-, androgen status, etc (R).
What can lower IL-6:
- A combination of Vitamin C (iHerb)(Amazon) (500mg dose) and E (iHerb)(Amazon) (800IU dose) inhibit the exercise induced IL-6 release by 50%. But vitamin C (500mg) on its own didn’t have the same effect (R).
- Creatine (R). (iHerb)(Amazon)
- HMB (R). (iHerb)(Amazon)
- Vitamin D (R). (iHerb)(Amazon)
- DHEA (iHerb)(Amazon)
- Curcumin (iHerb)(Amazon)
- Berberine (iHerb)(Amazon)
- Proper exercise
- Cinnamon (iHerb)(Amazon)
- Zinc (iHerb)(Amazon)
- Magnesium (iHerb)(Amazon)
Getting an increase in IL-6 from proper exercise (short and intense) is not a problem, but deliberately trying to boost it is not a good idea. In most cases IL-6 is already elevated due to endotoxins, too much PUFA consumption, excess adipose tissue, undereating, overeating, etc. Plus, the “fat loss benefit” from IL-6 is due to increased lipolysis in visceral fat and muscles, and this will only lead to fatty liver and insulin resistance, not actual fat loss.
IL-6 is lowered when carbs are consumed and carbs/insulin are highly anabolic. IL-6 does seem to play a role in satellite cell activation for hypertrophy, but in this case, more is not better, because things that lower IL-6, like vitamin D, HMB, carbohydrates, DHEA, etc., all have a positive effect on muscle mass, function, fat loss, etc.
Although anti-oxidant supplementation might interfere with the positive exercise induced adaptions, an excess of IL-6 and other inflammatory markers will be more catabolic than neutral, and things like vitamin E and aspirin will have an anabolic effect in people with elevated inflammation. This is seen in older men where aspirin has an anabolic effect due to lowering inflammation by inhibiting the COX enzyme.
The proper approach would be to have low baseline inflammation, which proper exercise and nutrition will help with, and train short and intense. This approach will keep your baseline IL-6 low and elevate your exercise induced IL-6 by less than 5 fold, which would then return to normal within 1 hour after training.
Before training I make sure my glycogen stores are full and I might also ingest some carbs during my workout depending on the intensity and duration of my session and then post-workout I have a big protein and carb meal to lower IL-6 and cortisol. This way I still benefit from IL-6 acutely and keep all the negative effects of chronically elevated IL-6 to a bare minimum.