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Inflammatory cytokine

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Proinflammatory cytokines are cytokines that are important in cell signaling and promote systemic inflammation. They are produced predominantly by activated macrophages and are involved in the upregulation of inflammatory reactions.[1] In contrast to anti-inflammatory cytokines, which promote healing and reduce inflammation, proinflammatory cytokines act to make a disease worse. For patients with harmful excess inflammatory reactions, anticytokine therapies include neutralizing antibodies, serving as soluble receptors and receptor antagonists, and inhibiting proteases.[2] Proinflammatory cytokines arise from genes that code for the translation of small mediator molecules that induce a response after upregulation. For example, chemokines are a class of genes that are proinflammatory. IL-1,[3] TNF alpha, and chemokines are examples of proinflammatory cytokines.[4]

Proinflammatory cytokines work with other important molecules from the immune system, such as neutrophils and leukocytes, in generating an immune response. This proinflammatory cytokine-mediated inflammation generates a collection of gene products in response to a trigger of a foreign body. However, excessive amounts of proinflammatory cytokines have been shown to cause detrimental effects, such as chronic systemic elevations in the body.[5] A lack of regulation in the release of these cytokines has been linked to different diseases, such as atherosclerosis and cancer. There are further implications that the misregulation of proinflammatory cytokines is also linked to depression and other neurologically related effects to the body[3]. It is important that the regulation between proinflammatory and anti-inflammatory cytokines stay balanced, as it could alter one's susceptibility to a disease. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α).[6] Recent therapies have looked into blocking proinflammatory cytokines in order to prevent the attack of these cytokines against our own bodies.

Function

Proinflammatory cytokines are used to activate neutrophils. Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α function to be a part of pathological pain. These cytokines can have multiple functions in multiple locations.[1] While IL-1β is released by monocytes and macrophages, it is also present in nocieptive DRG neurons. IL-6, on the other hand plays a role in neuronal reaction to an injury. TNF-α is a well known proinflammatory cytokine present in neurons and the glia. TNF-α is often involved in different signaling pathways to regulate apoptosis in the cells.

Negative impacts

Due to their proinflammatory action, proinflammatory cytokines tend to make a disease worse by causing fever, inflammation, tissue destruction, and in some cases, even shock and death.[3]

Detriments in the kidney

Proinflammatory cytokines affect functions of transporters and ion channels from the nephron. As a result, there is a change in the activity of the potassium ion (K+) channels that changes the transepithelial transport of solutes and water in the kidney.[7] The kidney proximal tubule cells produce proinflammatory cytokines in response to lipopolysaccaride. Proinflammatory cytokines affect the renal K+ channels. Interferon-gamma causes delayed suppression and acute stimulation of the 40 pS K+ channel. Also, TGF-beta activates the KCa3.1 K+ channel, which could be involved the detrimental effects of renal fibrosis.

Impact on graft-vs-host disease

Graft-vs-host disease (GVHD) targets JAK 1 and 2, tyrosine kinase proteins required for signaling multiple cytokines. When these kinases are activated, signal proteins of the STAT family, which include transcription factors for target genes that serve proinflammatory roles, are phosphorylated.[8] The severity of GVHD is highly variable and is influenced by the amount of naive cells present in the environment along with other regulatory T cell, TH1, TH2 or TH17 phenotypes.[9] Both CD4 and CD8 IL-17 producing T cells have been shown to cause aTH1, causing tissue inflammation and resulting in severe GVHD.[10]

Tissue destruction in cystic fibrosis

Elevated proinflammatory cytokines cause hyperinflammation, the leading cause of lung tissue destruction in cystic fibrosis.[11] With such a strong inflammatory response and an elevated number of immune cells, lungs of cystic fibrosis patients cannot clear the bacteria and become more susceptible to infections. A high prevalence (40-70%) of patients with cystic fibrosis show signs of asthma, possibly due to the primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR).[12] CFTR-deficient T-helper cells create an inflammatory environment that has high concentrations of TNF-α, IL-8, and IL-13, which contributes to increased contractility of airway smooth muscle.

Inflammatory mechanisms for cardiovascular disease

Atherosclerosis induces a dysfunctional endothelium, which recruits immune cells that form lesions.The body creates proinflammatory mediators that cause inflammation after ligands present in the vasculature of the heart activate immune cells.[13]

Role in adipose tissue metabolism and obesity

Proinflammatory cytokines are also seen in adipose tissues. Adipocytes generate TNF-α and other interleukins. Cytokines derived from adipose tissue serve as remote regulators such as hormones. Studies have shown that TNF-α and IL-6 concentrations are elevated in obesity.[14] Obesity leaves an excess of nutrients for the body, thereby causing adipocytes to release more proinflammatory cytokines. Classically activated macrophages in the visceral fat accumulate in the fat tissues and continuously release proinflammatory cytokines, causing chronic inflammation in obese individuals.

Clinical implications

Reducing the biological activities of proinflammatory cytokines can reduce the brunt of attack from diseases.[3]

Blocking IL-1 or TNF-α has been highly successful in helping patients with rheumatoid arthritis, inflammatory bowel disease,[15] or graft-vs-host disease.[3] However, the strategy has not yet been successful in humans with sepsis.[3] Therapeutic effects of acupuncture may be related to the body's ability to suppress a range of proinflammatory cytokines such as tumor necrosis factor alpha, IL1B, interleukin 6, and interleukin 10.[16]

Histone deacetylate inhibitors (HDACi) have also been shown to suppress proinflammatory cytokine production and reduce graft-vs-host disease.

Recent studies have shown the ability of exercise to control oxidative stress and inflammation in cardiovascular disease.

References

  1. ^ a b Zhang JM, An J. "Cytokines, inflammation, and pain". International Anesthesiology Clinics. 45 (2): 27–37. doi:10.1097/aia.0b013e318034194e. PMID 17426506.
  2. ^ Scarpioni R, Ricardi M, Albertazzi V (Jan 2016). "Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage". World Journal of Nephrology. 5 (1): 66–75. doi:10.5527/wjn.v5.i1.66. PMC 4707170. PMID 26788465.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b c d e Dinarello CA (Aug 2000). "Proinflammatory cytokines". Chest. 118 (2): 503–8. doi:10.1378/chest.118.2.503. PMID 10936147.
  4. ^ Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS (Dec 2002). "Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?". Lancet. 360 (9348): 1831–7. doi:10.1016/S0140-6736(02)11772-7. PMID 12480361.
  5. ^ Scarpioni R, Ricardi M, Albertazzi V (Jan 2016). "Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage". World Journal of Nephrology. 5 (1): 66–75. doi:10.5527/wjn.v5.i1.66. PMC 4707170. PMID 26788465.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Sallam N, Laher I (2015-12-28). "Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases". Oxidative Medicine and Cellular Longevity. 2016: 7239639. doi:10.1155/2016/7239639. PMC 4707375. PMID 26823952.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ Nakamura K, Hayashi H, Kubokawa M (2015-10-05). "Proinflammatory Cytokines and Potassium Channels in the Kidney". Mediators of Inflammation. 2015: 362768. doi:10.1155/2015/362768. PMC 4609835. PMID 26508816.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Teshima T, Reddy P, Zeiser R (Jan 2016). "Acute Graft-versus-Host Disease: Novel Biological Insights". Biology of Blood and Marrow Transplantation. 22 (1): 11–6. doi:10.1016/j.bbmt.2015.10.001. PMID 26453971.
  9. ^ Henden AS, Hill GR (May 2015). "Cytokines in Graft-versus-Host Disease". Journal of Immunology. 194 (10): 4604–12. doi:10.4049/jimmunol.1500117. PMID 25934923.
  10. ^ van der Waart AB, van der Velden WJ, Blijlevens NM, Dolstra H (Jun 2014). "Targeting the IL17 pathway for the prevention of graft-versus-host disease". Biology of Blood and Marrow Transplantation. 20 (6): 752–9. doi:10.1016/j.bbmt.2014.02.007. PMID 24565991.
  11. ^ Bruscia EM, Bonfield TL (Mar 2016). "Innate and Adaptive Immunity in Cystic Fibrosis". Clinics in Chest Medicine. 37 (1): 17–29. doi:10.1016/j.ccm.2015.11.010. PMID 26857765.
  12. ^ McCuaig S, Martin JG (Apr 2013). "How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis". The Lancet. Respiratory Medicine. 1 (2): 137–47. doi:10.1016/s2213-2600(12)70058-9. PMID 24429094.
  13. ^ Slocum C, Kramer C, Genco CA (Jan 2016). "Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis". Journal of Internal Medicine. doi:10.1111/joim.12476. PMID 26791914.
  14. ^ Coppack, Simon W. (2001-08-01). "Pro-inflammatory cytokines and adipose tissue". Proceedings of the Nutrition Society. 60 (03): 349–356. doi:10.1079/PNS2001110. ISSN 1475-2719.
  15. ^ Strober W, Fuss IJ (May 2011). "Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases". Gastroenterology. 140 (6): 1756–67. doi:10.1053/j.gastro.2011.02.016. PMID 21530742.
  16. ^ Wang XM, Walitt B, Saligan L, Tiwari AF, Cheung CW, Zhang ZJ (Mar 2015). "Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy". Cytokine. 72 (1): 86–96. doi:10.1016/j.cyto.2014.12.006. PMID 25573802. Even acupuncture may have therapeutic potential considering its effects on suppressing proinflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-10
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