Proinflammatory cytokine

A proinflammatory cytokine or more simply an inflammatory cytokine is a type of signaling molecule (a cytokine) that is excreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor (TNF), interferon gamma (IFN-gamma), and granulocyte-macrophage colony stimulating factor and play an important role in mediating the innate immune response. Inflammatory cytokines are predominately produced by and involved in the upregulation of inflammatory reactions.

Excessive chronic production of inflammatory cytokines contribute to inflammatory diseases, that have been linked to different diseases, such as atherosclerosis and cancer. Dysregulation has also been linked to depression and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.

Therapies to treat inflammatory diseases include monoclonal antibodies that either neutralize inflammatory cytokines or their receptors.

Definition

A proinflammatory cytokine or an inflammatory cytokine is a type of cytokine (signaling molecule) that is excreted from immune cells and certain other cell types that promotes inflammation. Inflammatory cytokines are predominately produced by helper T cells (Th) and macrophages and involved in the upregulation of inflammatory reactions.[1] Therapies to treat inflammatory diseases include monoclonal antibodies that either neutralize inflammatory cytokines or their receptors.[2]

Proinflammatory cytokines include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor (TNF), interferon gamma (IFN-gamma), and granulocyte-macrophage colony stimulating factor.[3]

Function

Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defence against pathogens mediating the innate immune response. Some inflammatory cytokines have additional roles such as acting as growth factors.[4] Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α also trigger pathological pain.[1] While IL-1β is released by monocytes and macrophages, it is also present in nocieptive DRG neurons. IL-6 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. Excessive chronic production of inflammatory cytokines contribute to inflammatory diseases.[5] that have been linked to different diseases, such as atherosclerosis and cancer. Dysregulation of proinflammatory cytokines have also been linked to depression and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.[6]

Negative impacts

Due to its proinflammatory action, a proinflammatory cytokine tends to make the disease itself or the symptoms correlated to a disease worse by causing fever, inflammation, tissue destruction, and in some cases, even shock and death.[7] Excessive amounts of proinflammatory cytokines have been shown to cause detrimental effects[5] Dysregulation of proinflammatory cytokines has also been linked to depression and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.[6]

In the kidney

A proinflammatory cytokine affects 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.[8] 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.

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.[9] 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.[10] Both CD4 and CD8 IL-17 producing T cells have been shown to cause aTH1, causing tissue inflammation and resulting in severe GVHD.[11]

In cystic fibrosis

A proinflammatory cytokine causes hyperinflammation, the leading cause of lung tissue destruction in cystic fibrosis.[12] 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).[13] 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.

In cardiovascular disease

Atherosclerosis induces a dysfunctional endothelium, which recruits immune cells that form lesions. Proinflammatory mediators cause inflammation after ligands in the heart vasculature octivate immune cells.[14] Recent studies have shown the ability of exercise to control oxidative stress and inflammation in cardiovascular disease.

In adipose tissue metabolism and obesity

A proinflammatory cytokine may be present 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.[15] 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 activity a proinflammatory cytokine can reduce the brunt of attack from diseases.[7]

Blocking IL-1 or TNF-α has been highly successful in helping patients with rheumatoid arthritis, inflammatory bowel disease,[16] or graft-vs-host disease.[7] However, the strategy has not yet been successful in humans with sepsis.[7] 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.[17]

Histone deacetylate inhibitors (HDACi) can suppress proinflammatory cytokine production and reduce graft-vs-host disease.

References

  1. 1 2 Zhang JM, An J (2007). "Cytokines, inflammation, and pain". International Anesthesiology Clinics. 45 (2): 27–37. PMC 2785020 Freely accessible. PMID 17426506. doi:10.1097/aia.0b013e318034194e.
  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. PMC 4707170 Freely accessible. PMID 26788465. doi:10.5527/wjn.v5.i1.66.
  3. ↑ Cavaillon JM (2001). "Pro- versus anti-inflammatory cytokines: myth or reality". Cellular and Molecular Biology (Noisy-le-Grand, France). 47 (4): 695–702. PMID 11502077.
  4. ↑ Fitzgerald KA, O'Neill LA, Gearing AJ, Callard RE (2001). The Cytokine Factsbook (2nd ed.). San Diego: Academic Press. p. 2. ISBN 978-0-12-155142-1.
  5. 1 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. PMC 4707170 Freely accessible. PMID 26788465. doi:10.5527/wjn.v5.i1.66.
  6. 1 2 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. PMC 4707375 Freely accessible. PMID 26823952. doi:10.1155/2016/7239639.
  7. 1 2 3 4 Dinarello CA (August 2000). "Proinflammatory cytokines". Chest. 118 (2): 503–8. PMID 10936147. doi:10.1378/chest.118.2.503.
  8. ↑ Nakamura K, Hayashi H, Kubokawa M (2015-10-05). "Proinflammatory Cytokines and Potassium Channels in the Kidney". Mediators of Inflammation. 2015: 362768. PMC 4609835 Freely accessible. PMID 26508816. doi:10.1155/2015/362768.
  9. ↑ 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. PMID 26453971. doi:10.1016/j.bbmt.2015.10.001.
  10. ↑ Henden AS, Hill GR (May 2015). "Cytokines in Graft-versus-Host Disease". Journal of Immunology. 194 (10): 4604–12. PMID 25934923. doi:10.4049/jimmunol.1500117.
  11. ↑ 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. PMID 24565991. doi:10.1016/j.bbmt.2014.02.007.
  12. ↑ Bruscia EM, Bonfield TL (Mar 2016). "Innate and Adaptive Immunity in Cystic Fibrosis". Clinics in Chest Medicine. 37 (1): 17–29. PMID 26857765. doi:10.1016/j.ccm.2015.11.010.
  13. ↑ 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. PMID 24429094. doi:10.1016/s2213-2600(12)70058-9.
  14. ↑ 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. 280: 114–28. PMID 26791914. doi:10.1111/joim.12476.
  15. ↑ Coppack, Simon W. (2001-08-01). "Pro-inflammatory cytokines and adipose tissue". Proceedings of the Nutrition Society. 60 (03): 349–356. ISSN 1475-2719. doi:10.1079/PNS2001110.
  16. ↑ Strober W, Fuss IJ (May 2011). "Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases". Gastroenterology. 140 (6): 1756–67. PMC 3773507 Freely accessible. PMID 21530742. doi:10.1053/j.gastro.2011.02.016.
  17. ↑ 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. PMC 4750385 Freely accessible. PMID 25573802. doi:10.1016/j.cyto.2014.12.006. 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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