What is Cellular Inflammation?

Dr. Sears' Blog: What is Cellular Inflammation?

People (including virtually all physicians) are constantly confused what cellular inflammation is. So I decided to take the opportunity to explain the concept in more detail.

There are two types of inflammation. The first type is classical inflammation, which generates the inflammatory response we associate with pain such as, heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain. Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body.

Definition of Cellular Inflammation

The definition of cellular inflammation is increased activity of the gene transcription factor know as Nuclear Factor-kappaB (NF-κB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system. Although the innate immune system is the most primitive part of our immune response, it has been resistant to study without recent breakthroughs in molecular biology. In fact, the 2011 Nobel Prize in Medicine was awarded for the earliest studies on the innate immune system and its implications in the development of chronic disease.

There are several extracellular events through which NF-κB can be activated by distinct mechanisms. These include microbial invasion recognized by toll-like receptors (TLR), generation of reactive oxygen species (ROS), cellular generation of inflammatory eicosanoids, and interaction with inflammatory cytokines via defined cell surface receptors. We also know that several of these initiating events are modulated by dietary factors. This also means that appropriate use of the diet can either turn on or turn off the activation of NF-κB. This new knowledge is the foundation of anti-inflammatory nutrition (1-3).

Understanding Cellular Inflammation

Although the innate immune system is exceptionally complex, it can be illustrated in a relatively simple diagram as shown below in Figure 1.

Figure 1. Simplified View of the Innate Immune System

Essential fatty acids are the most powerful modulators of NF-κB. In particular, the omega-6 fatty acid arachidonic acid (AA) activates NF-κB, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) does not (4). Recent work suggests that a subgroup of eicosanoids known as leukotrienes that are derived from AA may play a significant factor in NF-κB activation (5,6)

Extracellular inflammatory cytokines can also activate NF-κB by their interaction with specific receptors on the cell surface. The primary cytokine that activates NF-κB is tumor necrosis factor (TNF) (7). Toll-like receptors (TLR) are another starting point for the activation of NF-κB. In particular, TLR-4 is sensitive to dietary saturated fatty acids (8). The binding of saturated fatty acids to TLR-4 can be inhibited by omega-3 fatty acids such as EPA. Finally ROS either induced by ionizing radiation or by excess free radical formation are additional activators of NF-κB (9).

Anti-inflammatory Nutrition To Inhibit Cellular Inflammation

Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB.

The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane thus reducing the formation of leukotrienes that can activate NF-κB. Having the patient follow an anti-inflammatory diet, such as the Zone Diet coupled with the simultaneous lowering omega-6 fatty acid intake are the primary dietary strategies to accomplish this goal (1-3).

Another effective dietary approach (and often easier for the patient to comply with) is the dietary supplementation with adequate levels of high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. These omega-3 fatty acids taken at high enough levels will lower AA levels and increase EPA levels. This change of the AA/EPA ratio in the cell membrane will reduce the likelihood of the formation of inflammatory leukotrienes that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those from EPA are non-inflammatory. The increased intake of omega-3 fatty acids is also a dietary approach that can activate the anti-inflammatory gene transcription factor PPAR-γ (10-12), decrease the formation of ROS (13) and decrease the binding of saturated fatty acids to TLR-4 (14). This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation.

A third dietary approach is the adequate intake of dietary polyphenols. These are compounds that give fruits and vegetables their color. At high levels they are powerful anti-oxidants to reduce the generation of ROS (15). They can also inhibit the activation of NF-κB (16).

Finally, the least effective dietary strategy (but still useful) is the reduction of dietary saturated fat intake. This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane (8,14).

Obviously, the greater the number of these dietary strategies implemented by the patient, the greater the overall effect on reducing cellular inflammation.

Clinical Measurement of Cellular Inflammation

Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane.

As described above, the leukotrienes derived from AA are powerful modulators of NF-κB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-κB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane (17). Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-κB activation.

The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-κB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-κB. As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-κB activation. However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-κB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage.

In Summary

I believe the future of medicine lies in the control of cellular inflammation. This is most effectively accomplished by the constant application of anti-inflammatory nutrition. The success of such dietary interventions can be measured clinically by the reduction of the AA/EPA ratio in the blood.


  1. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005).
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008).
  3. Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011).
  4. Camandola S, Leonarduzzi G,Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229:643-647 (1996).
  5. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4:e7250 (2009).
  6. Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17:1657-1663 (2009).
  7. Min JK, Kim YM, Kim SW, Kwon MC, Kong YY, Hwang IK, Won MH, Rho J, and Kwon YG. “TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells.” J Immunol 175: 531-540 (2005).
  8. Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010).
  9. Bubici C, Papa S, Dean K, and Franzoso G. “Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.” Oncogene 25: 6731-6748 (2006).
  10. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67: 867-874 (2005).
  11. Kawashima A, Harada T, Imada K, Yano T, and Mizuguchi K. “Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.” Prostaglandins LeukotEssent Fatty Acids 79: 59-65 (2008).
  12. Chambrier C, Bastard JP, Rieusset J, Chevillotte E, Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville M, and Vidal H. “Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.” Obes Res 10: 518-525 (2002).
  13. Mas E, Woodman RJ, Burke V, Puddey IB, Beilin LJ, Durand T, and Mori TA. “The omega-3 fatty acids EPA and DHA decrease plasma F(2)-isoprostanes.” Free Radic Res 44: 983-990 (2010).
  14. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, and Hwang DH. “Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.” J Lipid Res 44: 479-486 (2003).
  15. Crispo JA, Ansell DR, Piche M, Eibl JK, Khaper N, Ross GM, and Tai TC. “Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells.” Can J Physiol Pharmacol 88: 429-438 (2010).
  16. Romier B, Van De Walle J, During A, Larondelle Y, and Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008).
  17. Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185-1194 (2010).

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About Dr. Barry Sears

Dr. Barry Sears is a leading authority on the impact of the diet on hormonal response, genetic expression, and inflammation. A former research scientist at the Boston University School of Medicine and the Massachusetts Institute of Technology, Dr. Sears has dedicated his research efforts over the past 45 years to the study of lipids. He has published 40 scientific articles and holds 14 U.S. patents in the areas of intravenous drug delivery systems and hormonal regulation for the treatment of cardiovascular disease. He has also written 14 books, including the New York Times #1 best-seller, The Zone, which have sold more than 6 million copies in the U.S. and have been translated into 22 different languages.


  1. Cynthia

    My daughter has ushers syndrome .
    I would like information on any supplements or diet supplements that can help reduce the inflamation at the cellular level to help her control her Retinitis
    pigmentosa .
    Thank you in advance .

  2. Jim Miller

    It is refreshing to finally have someone in the medical field tell us exactly what cellular inflammation is and its potentially dire consequences. I work as an independent researcher in the field of pet nutrition and am always amazed at the lack of knowledge that allopathic veterinarians have regarding the connection between cellular inflammation and chronic disease – almost all of which is caused by the ingestion of biologically inappropriate foods, namely, highly refined and processed grains and carbohydrates. I plan to read Dr. Sears books as the information here is applicable to other species besides human beings.

    • Barry Sears

      Much of the information on diet-induced inflammation is so recent that most physicians were never taught it while they were in training.

  3. Mark hofer

    He of bladder cancer since 2009. Cystectomy. Students pouch. No cancer since. Two weeks ago per cytology inflamed cells possibly cancer cells. Do you think that if I follow your suggestions this will dissipate? Did a fish test also that was negative.

    • Barry Sears

      The clinical data is clear that high-dose omega-3 fatty acids (greater than 5 grams of EPA and DHA per day) will reduce inflammatory cytokines.

  4. Mark

    I was on the Zone diet about 20 years ago. I had great success, but over the years I have gained weight back. I have a wife who is type 2 diabetic who is having trouble controlling her insulin level. The main reason for this inquiry is a daughter who is 40 years old and suffers from chronic fibromyalgia, over weight, and upper spine problems caused by spurs on her spine. Her blood pressure is also elevated. I can see my daughter possibly an invalid in 5 years.

    I am requesting some direction in how to help my daughter turn her life around and also how to help my wife reduce her insulin levels and me to loose weight. Could you please give me some direction?



    • Barry Sears

      I would suggest calling Dave Schreck in our technical support section to provide some appropriate dietary advice. Her wide range of inflammatory conditions would suggest that a strict anti-inflammatory nutrition program would be of benefit.

  5. Kim

    Hi Dr Sears, logically anti-inflammatory nutrition will help alleviate psoriasis due to Interleukins IL17 for example?

    • Barry Sears

      Psoriasis is driven by high levels of leukotrienes that can reduced either by reducing AA formation or increase EPA and DHA intake. Both are at the foundation of anti-inflammatory nutrition.

  6. Fred Wittig

    We suspect that many health challenges may be caused by an anaerobic infection/inflamation. Renal failure, chronic arthritis and possibly almost all invaders that are anaerobic.

    However they seem to have no defense against the very unstable single oxygen atom, O1 not O2. This O1 tags along with hydrogen peroxide, Ozone, Lypo Spheric Vitamin C, CLO2 and others.

    Since this therapy is so simple, risk free, and almost no cost we would recommend doing a round first and then see what you have.
    This would be an element of the “Terrain Approach” to wellness.

    • Barry Sears

      The entry of anaerobic microbes into the blood will always induce significant inflammatory responses via toll-like receptors activating NF-kB.. One approach is to reduce gut permeability using a dietary combination of prebiotics and polyphenols to strengthen the tight junctions the mucosal level to limit entry of anaerobic microbes or their microbial fragments. Another is to activate the Nrf2 gene using high-dose polyphenols to induce increased expression of additional anti-oxidant enzymes that will reduce the levels of unstable free radicals.

  7. Dr. Sears

    You are partially correct that certain cells (like the epithelial cells that the line the gut, blood vessels and the blood-brain-barrier) due become more permeable due to increased inflammation. This comes from an increase in leukotriene production that increases cell permeability. This increased permeability allows biological compounds to enter the cell that normally would be restricted. On the other hand, if the cell’s garage disposal system (autophagy) is compromised, cellular debris builds up and that can cause internal inflammation. Both situations are bad for the normal functioning of any cell. The best way to correct both is to decrease the AA/EPA ratio in the cell membrane thus reducing leukotriene formation and increasing the resolution response that activates autophagy.


      Thank you Dr Sears. I have seen miracle cure of severe scalp psoriasis, plaque psoriasis and the life threatening Erythrodermic Psoriasis. Regards, LK Kim

  8. Gina

    I really enjoyed reading about this, took some notes.

    But as said above, we do need a bit more info on what type of food and what is found where, you know, eat more of this and less of that, you will find XX in this, try to avoid that….



  9. Mark

    I definitely like this article more than so many others out there that are either nonspecific or without citations. I could do without citations of your own work, though. Short of trying to check the references on my own, this would increase the credibility even further for me.

  10. Maria

    I don’t understand the information. I need simple words.
    what diet should i have in order not to have cellular inflammation?
    I eat lots of fruits vegetables not that many and had lost 23 lbs, slowly but I am doing it.
    I am 70 years old and trying to keep my self healthy
    what should I do?

  11. Sally

    Need more information. My son has been sick since 2011 with a headache everyday all day

    • Bruce

      Dear Sally:

      Your son is suffering unnecessarily. Most chronic headaches are related to diet and lifestyle. He needs to have further testing done, outside of modern medical testing.

      • Mary

        Dear Dr. Sears,

        My son is obese and has tried to lose weight, but he has gone in many diets and didn’t have any success. Could you please tell me if cellular inflammation might be the cause. Could you give me any suggestions as what to do about it. Drs. don’t seem to be able to him.

        Thank you very much


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