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Cytokines and eicosanoids

Last updated: December 2, 2020

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.

Cytokines

General considerations

Nomenclature

Functional classification

Cytokines are classified into proinflammatory and anti-inflammatory. An imbalance between these two groups of cytokines results in immune-mediated diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis).

References:[1][2][3]

Interleukins

Overview of interleukins
Interleukin Secreted by

Targets and effect

Therapeutic significance
Interleukin-1 (IL-1)
Interleukin-2 (IL-2) [4]
Interleukin-3 (IL-3)
  • N/A
Interleukin-4 (IL-4) [5]
Interleukin-5 (IL-5)
Interleukin-6 (IL-6)
Interleukin-7 (IL-7)
  • N/A
Interleukin-8 (IL-8)
  • N/A
Interleukin-10 (IL-10)
  • N/A
Interleukin-11 (IL-11)
Interleukin-12 (IL-12)
Interleukin-17 (IL-17)
Interleukin-24 (IL-24)
  • Takes part in tumor suppression
  • N/A

Interleukin-28 (IL-28)

Interleukin-29 (IL-29)

  • N/A
Interleukin-32 (IL-32)
  • N/A

- 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

Think “Neutrophils are a cleaning aid (8)” to remember that Interleukin-8 attracts neutrophils to clear infection sites.

AMBOSS mnemonics 4 BEGinners help 2 put their mind at ease — Interleukin-4 stimulates growth of B cells, enables class switching to IgE and IgG and triggers T cell differentiation into Th2 (helper) cells.

IL-10 and TGF-β are both anTi-ENflammatory.

References:[7][8][9][10][11][12][13]

Interferons and tumor necrosis factor family

Interferons [10][11][12][13][14]

Overview of interferons
Interferon Mainly secreted by Function

Therapeutic use

Side effects [16]
Type I Interferon alpha (IFN-α)
  • First line of defense against all viral infections
  • Inhibits viral protein synthesis by activating ribonuclease L (leads to the degradation of cellular and viral mRNA)
  • Promotes the expression of MHC class I molecules, so that virus‑infected cells are rapidly recognized → activation of NK cells and cytotoxic T cells
  • Inhibits megakaryocyte stem cell differentiation and proliferation [19]
Interferon beta (IFN-β)
Type II Interferon gamma (IFN-γ)

Interferons interfere with cells with an altered genetic interface (virus-infected and malignant ones).

To remember the use of interferon-γ, think: “Interferon gamma for granulomatous diseases!”

Tumor necrosis factor superfamily [9][10][11][12][13]

Members of the tumor necrosis factor superfamily
Protein Mainly secreted by Functions Therapeutic significance
Cachectin (tumor necrosis factor; formerly tumor necrosis factor-alpha)
  • TNF inhibitors such as infliximab are used in the treatment of refractory chronic inflammatory systemic diseases (e.g., Crohn disease).

Lymphotoxin-alpha (formerly tumor necrosis factor-beta) [26]

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

Transforming growth factor family

Transforming growth factor family
TGF member Function
Transforming growth factor-β (TGF-β) [28][29]
  • Inhibits pro-inflammatory enzymes (e.g., macrophageal proteases)
  • Induces repair and remodelling of different tissues, including bone
  • Takes part in growth and differentiation of embryonic tissue cells and stem cells in the postnatal period
  • Stimulates antibody class switching to IgA [30]
Bone morphogenetic proteins [31]
Activins [36]
Inhibins [37]

IL-10 and TGF-β are both anTi-ENflammatory.

Eicosanoids

Overview

Arachidonic acid pathway

AA is further metabolized in two major pathways, derivatives of which are shown in the table below.

Derivatives of arachidonic pathway
Enzyme Intermediate Eicosanoid Function

Clinical relevance (analogs and inhibitors)

5-lipoxygenase

  • 5-HPETE
  • Leukotriene B4 (LTB4)
  • Leukotriene C4 (LTC4)
  • Bronchoconstriction
  • Increased capillary permeability
  • Leukotriene D4 (LTD4)
  • Leukotriene E4 (LTE4)

COX-1 and COX-2

  • Prostaglandin H2
  • Prostaglandin E1 (PGE1)
  • Relaxes vascular smooth muscle → vasodilation
  • Reduces gastric acid production
  • Stimulates production and secretion of mucous
  • Prostaglandin E2 (PGE2)
  • Thromboxane A2 (TXA2)
  • No specific inhibitors approved for use in the US
  • Prostacyclin (PGI2)

Leukotriene B4 (LTB4) functions as a neutrophil chemotactic agent: “You should call neutrophils B4 (“before”) any other cell”.

PGI2 = Platelet aGgregation Inhibitor PGE2 elevates body temperature: “fEvEr has 2 E's just like PGE2

References

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