Cytokines and eicosanoids

Summary

Cytokines are signaling proteins that modulate immune responses, inflammation, and hematopoietic cell proliferation and differentiation. They are mainly secreted by hematopoietic cells and can act in an autocrine, paracrine, or endocrine mode. They are classified into proinflammatory cytokines (interleukins 1, 6, 8, 12, and 18; interferons; and tumor necrosis factor) and anti-inflammatory cytokines (interleukins 4,10, 11, and 13; and transforming growth factor-beta). Proinflammatory cytokines induce fever and inflammation in response to infection or tissue injury, while anti-inflammatory cytokines suppress the immune system. Interferons are proinflammatory cytokines that are secreted by fibroblasts, leukocytes, cells infected by viruses in response to infection or neoplastic proliferation. Since interferons have antiviral, antimicrobial, and antitumor (antiproliferative) properties, they are used in the treatment of chronic viral infections (hepatitis B and hepatitis C), tumors (leukemia, Kaposi sarcoma), and autoimmune diseases (rheumatoid arthritis, systemic sclerosis).

Eicosanoids are proinflammatory and anti-inflammatory signaling molecules derived from arachidonic acid (AA) and include prostaglandins, leukotrienes, prostacyclins, and thromboxane A2.

Overview

Cytokines are signaling proteins that act on receptors and regulate the activation of cell differentiation, especially in the immune system.

References:[1][2][3]

Interleukins

Interleukin Secreted by

Targets and effect

Interleukin-1 (IL-1)
Interleukin-2 (IL-2)
Interleukin-3 (IL-3)
Interleukin-4 (IL-4)
Interleukin-5 (IL-5)
Interleukin-6 (IL-6)
Interleukin-7 (IL-7)
Interleukin-8 (IL-8)
Interleukin-10(IL-10)
Interleukin-11 (IL-11)
Interleukin-12(IL-12)
Interleukin-24 (IL-24)

Interleukin-28(IL-28)

Interleukin-29 (IL-29)

  • Dendritic cells
Interleukin-32 (IL-32)



Interleukins secreted by macrophages: IL-1, 6, 8, 12 (and TNF-α)
Interleukins secreted by all T cells: IL-2 and 3
Most important proinflammatory interleukins (endogenous pyrogens and main mediators of sepsis): IL-1 and 6 (and TNF-α)
Most important anti-inflammatory interleukin: IL-10
Promoters of differentiation of T cells to Th2: IL-2 and 4
Class switching interleukins: IL-4 and 5
Acute phase reactant stimulators: IL-6 and 11
Neutrophil chemotactic factor: IL-8 (chemokine)

Hot T-bone stEAK represents the effects of IL-1 through IL-6:
IL-1: promotes (hot) fever
IL-2: stimulates proliferation/differentiation of T cells
IL-3: stimulates proliferation of granulocytes and stem cells in the bone marrow
IL-4: stimulates class switching to IgE
IL-5: stimulates class switching to IgA
IL-6: stimulates the synthesis of aKute phase reactants

References:[4][4][5][6][7][8][9]

Interferons and tumor necrosis factor

Interferons

Interferon Secreted by Function

Therapeutic use

Interferon alpha (IFN-α)
  • Virus‑infected cells and malignant cells, especially leukocytes
Interferon beta (IFN-β)
Interferon gamma (IFN-γ)
  • Activates macrophages to increase phagocytosis (positive reinforcement)
  • Formation of granulomas (critical against mycobacterial infections)
  • Suppresses a Th2 response (negative feedback)
  • Promotes the expression of MHC class II molecules

Tumor necrosis factor

Secreted by Functions Therapeutic use
Tumor necrosis factor alpha (TNF-α; cachectin)
  • TNF‑α inhibitors such as infliximab are used in the treatment of refractory chronic inflammatory systemic diseases (e.g., Crohn disease).

Tumor necrosis factor beta (TNF-β; lymphotoxin)

Th1 lymphocytes secrete IFN-γ, which activates macrophages and is essential for the formation of tubercular granulomas.
Activated macrophages secrete TNF-α, which is essential for the maintenance of tubercular granulomas.

References:[10][11][12][13][14][15][16][17][18]

Eicosanoids

Enzyme Intermediate Eicosanoid Function

Clinical relevance

(analogs and inhibitors)

Arachidonic acid
  • Bronchoconstriction
  • Increased capillary permeability
  • Smooth muscle relaxation
  • Smooth muscle relaxation
  • Inflammation
    • Raises body temperature
    • Increases sensitivity to pain
  • Metabolism
  • Stomach
    • Decreases gastric acid secretion
    • Increases HCO3- and mucus secretion
  • Smooth muscle contraction

  • 1. Berger A. Science commentary: Th1 and Th2 responses: what are they?. BMJ. 2000; 321(7258): pp. 424–424. doi: 10.1136/bmj.321.7258.424.
  • 2. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000; 117(4): pp. 1162–1172. doi: 10.1378/chest.117.4.1162.
  • 3. Sino Biological. Anti-Inflammatory Cytokines List. http://www.sinobiological.com/Anti-inflammatory-cytokines-list.html. Updated January 1, 2018. Accessed December 30, 2018.
  • 4. Kaplan. USMLE Step 1 Lecture Notes 2016: Immunology and Microbiology. Kaplan Publishing; 2015.
  • 5. Panchbhavi VK. Bone Marrow Anatomy. In: Gest TR. Bone Marrow Anatomy. New York, NY: WebMD. https://emedicine.medscape.com/article/1968326. Updated November 29, 2017. Accessed December 19, 2017.
  • 6. Sino Biological. Interleukin Function / Function of Interleukin. http://www.sinobiological.com/interleukin-function-function-of-interleukin.html. Updated January 1, 2018. Accessed December 30, 2018.
  • 7. Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011; 127(3): pp. 701–721.e70. doi: 10.1016/j.jaci.2010.11.050.
  • 8. Li D. Cell-Mediated Immunity. https://step1.medbullets.com/immunology/105050/cell-mediated-immunity. Updated November 17, 2018. Accessed December 30, 2018.
  • 9. Sims NA, Jenkins BJ, Nakamura A, et al. Interleukin-11 receptor signaling is required for normal bone remodeling. J Bone Miner Res. 2005; 20(7): pp. 1093–1102. doi: 10.1359/jbmr.050209.
  • 10. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P . Molecular Biology of the Cell. New York, NY: Garland Science; 2002.
  • 11. Parkin J, Cohen B. An overview of the immune system. Lancet. 2001; 357(9270): pp. 1777–1789. doi: 10.1016/s0140-6736(00)04904-7.
  • 12. Dembic Z. The Cytokines of the Immune System. Academic Press; 2015.
  • 13. Drutskaya MS, Efimov GA, Kruglov AA, Kuprash DV, Nedospasov SA. Tumor necrosis factor, lymphotoxin and cancer. Life. 2010; 62(4): pp. 283–289. doi: 10.1002/iub.309.
  • 14. Lebrec H, Ponce R, Preston BD, Iles J, Born TL, Hooper M. Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk. Curr Med Res Opin. 2015; 31(3): pp. 557–574. doi: 10.1185/03007995.2015.1011778.
  • 15. Lin PL, Plessner HL, Voitenok NN, Flynn JL. Tumor necrosis factor and tuberculosis. J Investig Dermatol Symp Proc. 2007; 12(1): pp. 22–25. doi: 10.1038/sj.jidsymp.5650027.
  • 16. Harris J, Keane J. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol. 2010; 161(1): pp. 1–9. doi: 10.1111/j.1365-2249.2010.04146.x.
  • 17. Long R, Gardam M. Tumour necrosis factor-alpha inhibitors and the reactivation of latent tuberculosis infection. CMAJ. 2003; 168(9): pp. 1153–6. pmid: 12719321.
  • 18. Hong S. Connection between inflammation and carcinogenesis in gastrointestinal tract: Focus on TGF-β signaling. World J Gastroenterol. 2010; 16(17): p. 2080. doi: 10.3748/wjg.v16.i17.2080.
  • Katzung BG, Trevor AJ. Basic and Clinical Pharmacology 14E. McGraw-Hill Education / Medical; 2017.
last updated 09/21/2020
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