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. inteferon gamma (IFN gamma)

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)
  • Anti-inflammatory (immune suppression)
    • Inhibits activated macrophages, dendritic cells, and the inflammatory response
    • Reduces MHC class II expression and secretion of Th1 cytokines
  • N/A
Interleukin-11 (IL-11)
Interleukin-12 (IL-12)
  • Macrophages
Interleukin-17 (IL-17)
  • IL-17A antagonists (e.g., ixekizumab, secukinumab): psoriasis
Interleukin-24 (IL-24)
  • Takes part in tumor suppression
  • N/A

Interleukin-28 (IL-28)

Interleukin-29 (IL-29)

  • Dendritic cells
  • 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][14][11][12][13]

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)
  • Th1 and NK cells (when stimulated by IL-12 from macrophages or antigen contact)
  • Activates macrophages to increase phagocytosis (positive reinforcement) and NK to eliminate virus-infected target cells
  • Synergistic effect with tumor necrosis factor in stimulating macrophages to form granulomas (critical against mycobacterial infections)
  • Suppresses a Th2 response (negative feedback)
  • Promotes the expression of MHC class II molecules and antigen presentation in every cell
  • Stimulates antigen class switching to IgG3 [20]

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)
  • Activated macrophages
  • 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

  • A group of regulatory proteins with similar structure and target receptors that are involved in:
  • Dysregulation of TGF genes is implicated in the pathogenesis of autoimmune diseases and various types of cancers.
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]
  • Activate bone and cartilage formation and repair
  • Stimulate development of embryonic structures (e.g., foregut and hindgut, Mullerian duct) [32][33]
  • Stimulate white and brown adipose tissue development [34]
  • Recombinant BMP-2 and BMP-7 are used to stimulate bone formation, e.g., in orthopedic surgeries. [35]
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

  • Bronchoconstriction
  • Increased capillary permeability

COX-1 and COX-2

  • Relaxes vascular smooth muscle → vasodilation
  • Reduces gastric acid production
  • Stimulates production and secretion of mucous
  • Relaxes vascular smooth muscle → vasodilation
  • Increases uterine tone and softens the cervix during labor
  • Constricts (via EP1 and EP3 receptors) or dilates (via EP2 receptors) bronchi [38]
  • Inflammation
    • Raises body temperature
    • Increases sensitivity to pain
  • Metabolism
  • Stomach
    • Decreases gastric acid secretion
    • Increases HCO3- and mucus secretion
  • Smooth muscle contraction (e.g., increases uterine tone)
  • Relaxation of the ciliary muscle → increased uveoscleral outflow [39]
  • No specific inhibitors approved for use in the US

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

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last updated 11/10/2020
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