Blockade of TNF-alpha  (Tumor Necrosis Factor-alpha) Inhibits the Brain’s Response to Pain Before It Reduces Joint Pain

Blockers of TNF-alpha have become very effective treatments for the serious pain and swelling of Rheumatoid arthritis and similar painful inflammatory disorders during the past ten years. The speed at which TNF-alpha blockade is able to reduce pain intrigued researchers, who have published a new paper showing (through the use of blood-oxygen level-dependent [BOLD] fMRI imaging) that changes in the brain precede the relief of pain in the periphery.1

In fact, the researchers found that in as little as 24 hours after an infusion of a monoclonal antibody to TNF-alpha, nociceptive (pain) activity in areas of the brain that included the thalamus and somatosensoric cortex and also in the limbic system was blocked. This was before joint swelling and acute phase reactants in joints were affected by treatment. It worked the same in arthritic mice overexpressing human TNF-alpha that were treated with anti-TNF-alpha monoclonal antibodies. “Although it takes several weeks to observe a consistent and objective reduction of joint inflammation, many patients report on a rapid effect of TNF-alpha blockade on their subjective disease state.”1

When TNF-alpha Is Enough and When It Is Too Much

One big problem, however, in inhibiting TNF-alpha too strongly is that it increases the risk of infection, since TNF-alpha is an important component of the immune system. As noted in another paper,2 “[a]lthough therapeutic blockade of TNF-alpha worsens the prognosis in patients with abscesses and granulomatous infections, this strategy is highly beneficial in the case of chronic inflammatory conditions, including rheumatoid arthritis.” In other words, the ACUTE release of TNF-alpha in response to infection is generally appropriate, whereas CHRONIC elevated circulation levels of TNF-alpha often are not. For example, conditions that have been linked to increased chronic circulating levels of TNF-alpha include the neuroinflammation of postoperative cognitive decline,3endothelial dysfunction,4 bone loss in estrogen deficiency,5 and aging.6 Also, curiously, increased expression of TNF-alpha in response to LPS (a component of bacterial cell walls that activates the immune system) is associated with increased aggression and hostility in men, personality factors that have also been associated with an increased risk of cardiovascular disease.7 Persistence of inflammatory cytokines such as TNF-alpha can induce proatherogenic lipid patterns and insulin resistance.2 In fact, those with chronic inflammatory conditions such as rheumatoid arthritis or lupus have a higher mortality due to cardiovascular disease than the general population.2

Natural Substances That Inhibit TNF-alpha

The herb Cat’s claw (Uncaria tomentosa) is a “remarkably potent inhibitor” of TNF-alpha production.8 It is a widely used herbal remedy for inflammatory conditions such as arthritis. In one study,8 researchers found that in cell culture (using mouse macrophages), LPS increased TNF-alpha in the culture medium from 3 to 97 ng/ml. Cat’s claw suppressed TNF-alpha production by 65–85%, but (the paper reports) “at concentrations considerably lower than its antioxidant activity: freeze-dried EC50 = 1.2 ng/ml, micropulverized EC50 = 28 ng/ml.”

Glycine is a nutrient amino acid that was shown to reduce TNF-alpha production in response to LPS in monocytes from healthy human donors.9 In the same study, glycine also increased the expression of IL-10, an important anti-inflammatory cytokine. The authors9 also reported that glycine has been shown to protect against endotoxin shock (in the early phase) by inhibiting TNF-alpha production.

Both quercetin and resveratrol have been reported to attenuate TNF-alpha-mediated inflammation and insulin resistance in human adipocytes (fat cells), with quercetin being equally or more effective than resveratrol.10

Other natural inhibitors of TNF-alpha release or production include xanthohumol (a component of hops),11 fish oil (in a study of peripheral blood mononuclear cells of healthy men),12 and the opioid antagonist naltrexone,13 to name a few.


  1. Hess et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA 108(9):3731-6 (2011).
  2. Popa et al. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 48:751-62 (2007).
  3. Terrando et al. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci 107(47):20518-22 (2010).
  4. Speciale et al. Cyanidin-3-O-glucoside protection against TNF-alpha-induced endothelial dysfunction: involvement of nuclear factor kappaB signaling. J Agric Food Chem 58:12048-54 (2010).
  5. Cenci et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106(10):1229-37 (2000).
  6. de Gonzalo-Calvo et al. Differential inflammatory responses in aging and disease: TNF-alpha and IL-6 as possible biomarkers. Free Radic Biol Med 49:733-7 (2010).
  7. Suarez et al. The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men. Brain Behav Immun 16:675-84 (2002).
  8. Sandoval et al. Cat’s claw inhibits TNFalpha production and scavenges free radicals: role in cytoprotection. Free Radic Biol Med 29(1):71-8 (2000).
  9. Spittler et al. Immunomodulatory effects of glycine on LPS- treated monocytes: reduced TNF-alpha production and accelerated IL-10 expression. FASEB J 13:563-71 (1999).
  10. Chuang et al. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-alpha-mediated inflammation and insulin resistance in primary human adipocytes. Am J Clin Nutr 92:1511-21 (2010).
  11. Lupinacci et al. Xanthohumol from hop (Humulus lupulus L.) is an efficient inhibitor of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha release in LPS-stimulated RAW 264.7 mouse macrophages and U937 human monocytes. J Agric Food Chem 57:7274-81 (2009).
  12. Grimble et al. The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor alpha production. Am J Clin Nutr 76:454-9 (2002).
  13. Greeneltch et al. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. Brain Behav Immun 18:476-84 (2004).