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Inflammatory cytokine

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An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted 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-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly 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

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An inflammatory cytokine is a type of cytokine (a signaling molecule) that is secreted from immune cells and certain other cell types that promotes inflammation. Inflammatory cytokines are predominantly produced by T helper 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]

Inflammatory cytokines include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF).[3]

Function

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Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defence against pathogens mediating the innate immune response.[4] Some inflammatory cytokines have additional roles such as acting as growth factors.[5] 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 nociceptive 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.[citation needed] Excessive chronic production of inflammatory cytokines contribute to inflammatory diseases.[2] 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

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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[2]

In the kidney

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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 lipopolysaccharide. Proinflammatory cytokines affect the renal K+ channels. IFNγ causes delayed suppression and acute stimulation of the 40 pS K+ channel. Also, transforming growth factor beta 1 (TGF-β1) activates the calcium-activated potassium channel (KCa3.1) which could be involved the detrimental effects of renal fibrosis.[citation needed]

Graft-vs-host disease

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Graft-versus-host disease (GvHD) targets JAK 1 and 2, the human tyrosine kinase protein required for signaling in multiple cytokines. When these kinases are activated, signal proteins of the signal transducer and activator of transcription (STAT) protein 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 native cells present in the environment along with other regulatory T cells, 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

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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.[citation needed]

In cardiovascular disease

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

In adipose tissue metabolism and obesity

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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][16][17] 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.[citation needed]

In osteoarthritis

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TNF-α, IL-1 and IL-6 have been found to play a pivotal role in cartilage matrix degradation and bone resorption in osteoarthritis.[18] Animal studies indicate that inflammatory cytokines may stimulate chondrocytes to release cartilage-degrading protease in osteoarthritis. This finding does not, however, necessarily translate to Homo sapiens, as osteoarthritis in humans is considered to be more complex than any animal model.[19]

Fatigue

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Cytokines have key roles in inflammation, which is seen as a causal mechanism in fatigue.[20]

Clinical implications

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Reducing the biological activity of 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,[21] or graft-vs-host disease (GvHD).[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 (TNF-α), IL-1B, IL-6, and IL-10.[22]

Estrogen has been shown to promote healing by decrease the production of various proinflammatory cytokines like IL-6,[23] TNF-α,[24] and macrophage migration inhibitory factor (MIF). Increased MIF levels are often found at the site of chronic non-healing ulcers, with those levels dropping significantly with successful healing. A 2005 review of current experimental data shows that "estrogen regulates healing almost exclusively via MIF down-regulation and identifies novel MIF-regulated gene targets and clusters associated with aberrant healing." By down-regulating MIF, estrogen can promote healing, as correlated by clinical studies on aging skin and skin wounds. Unfortunately, estrogen-therapy has known carcinogenic effects[25] as mentioned by the American Cancer Society (increased incidences of breast cancer in women who undergo HRT). However, scientists could make important discoveries in the future by studying "downstream effects on genes/factors that mediate the effects of estrogen on healing."[26]

Histone deacetylate inhibitors (HDACi) can suppress proinflammatory cytokine production and reduce GvHD.[citation needed]

Some research also suggest an immunoregulatory effect of vitamin D, which has been shown to reduce the secretion of specific inflammatory cytokines.[27][28]

References

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  2. ^ a b c 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 (inactive 1 November 2024). PMC 4707170. PMID 26788465.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
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  17. ^ Virdis A, Colucci R, Bernardini N, Masi S (2019). "Microvascular Endothelial Dysfunction in Human Obesity: Role of TNF-α". The Journal of Clinical Endocrinology and Metabolism. 104 (2): 341–348. doi:10.1210/jc.2018-00512. PMID 30165404.
  18. ^ Wang, Tiantian; He, Chengqi (December 2018). "Pro-inflammatory cytokines: The link between obesity and osteoarthritis". Cytokine & Growth Factor Reviews. 44: 38–50. doi:10.1016/j.cytogfr.2018.10.002. PMID 30340925. S2CID 53009998.
  19. ^ Goldring, Mary B. (January 1999). "The Role of Cytokines as Inflammatory Mediators in Osteoarthritis: Lessons from Animal Models". Connective Tissue Research. 40 (1): 1–11. doi:10.3109/03008209909005273. PMID 10770646.
  20. ^ Karshikoff, Bianka; Sundelin, Tina; Lasselin, Julie (2017). "Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms". Frontiers in Immunology. 8: 21. doi:10.3389/fimmu.2017.00021. PMC 5247454. PMID 28163706.
  21. ^ Strober, Warren; Fuss, Ivan J. (May 2011). "Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases". Gastroenterology. 140 (6): 1756–1767.e1. doi:10.1053/j.gastro.2011.02.016. PMC 3773507. PMID 21530742.
  22. ^ Wang, Xiao-Min; Walitt, Brian; Saligan, Leorey; Tiwari, Agnes FY; Cheung, Chi Wai; Zhang, Zhang-Jin (March 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. PMC 4750385. PMID 25573802.
  23. ^ Canellada, Andrea; Alvarez, Irene; Berod, Luciana; Gentile, Teresa (September 2008). "Estrogen and progesterone regulate the IL-6 signal transduction pathway in antibody secreting cells". The Journal of Steroid Biochemistry and Molecular Biology. 111 (3–5): 255–261. doi:10.1016/j.jsbmb.2008.06.009. PMID 18619543. S2CID 24957064.
  24. ^ Fortini, Francesca; Vieceli Dalla Sega, Francesco; Caliceti, Cristiana; Lambertini, Elisabetta; Pannuti, Antonio; Peiffer, Daniel S.; Balla, Cristina; Rizzo, Paola (May 2019). "Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway". The Journal of Steroid Biochemistry and Molecular Biology. 189: 87–100. doi:10.1016/j.jsbmb.2019.02.008. hdl:11392/2405957. PMID 30817989. S2CID 72334147.
  25. ^ "Hormone Therapy for Breast Cancer | American Cancer Society". www.cancer.org. Retrieved 2019-02-27.
  26. ^ "Hormonal Influences on Wound Healing: A Review of Current Experimental Data". Wounds Research. Retrieved 2019-02-27.
  27. ^ Sharifi, Amrollah; Vahedi, Homayoon; Nedjat, Saharnaz; Rafiei, Hossein; Hosseinzadeh-Attar, Mohammad Javad (October 2019). "Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial". APMIS. 127 (10): 681–687. doi:10.1111/apm.12982. PMID 31274211. S2CID 195806132.
  28. ^ Ohaegbulam, Kim C.; Swalih, Mohamed; Patel, Pranavkumar; Smith, Miriam A.; Perrin, Richard (September 2020). "Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series". American Journal of Therapeutics. 27 (5): e485–e490. doi:10.1097/MJT.0000000000001222. PMC 7473790. PMID 32804682.
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