Cytokines and eicosanoids

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 antiinflammatory 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 antiinflammatory signaling molecules derived from arachidonic acid (AA) and include prostaglandins, leukotrienes, prostacyclins, and thromboxane A2.

General considerations

• Cytokines are small extracellular signaling proteins that are secreted mainly by immune cells (especially T lymphocytes) in response to a stimulus such as infection, ischemia, or injury.
• Act on receptors to modulate immune responses, inflammation, and hematopoietic cellular proliferation and differentiation.
• Target receptor can be located on:
  • The cell that secreted them (autocrine action)
  • Local hematopoietic cells (paracrine action)
  • Distant hematopoietic cells (endocrine action)

Nomenclature

• Interleukins: cytokines secreted by a leukocyte that acts on another type of leukocyte
• Lymphokines: cytokines secreted by lymphocytes
• Monokines: cytokines secreted by monocytes
• Chemokines: cytokines that have chemotactic activities

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).

• Proinflammatory cytokines (Th1 cytokines): stimulate the immune system
  • Interleukins 1, 6, 8, 12, 18, IFN-γ, and tumor necrosis factor (TNF)
  • Induce fever, inflammation, and tissue destruction in response to infection, injury, or ischemia
  • Cytokine storm: an excessive release of proinflammatory cytokines that causes hyperactivation of immune system and exaggerated immune response leading to multiorgan dysfunction
• Antiinflammatory cytokines (Th2 cytokines): suppress the immune system
  • Interleukins 4,10, 11,13, TGFβ, and receptor antagonists of IL-1 and cachectin
  • Suppress proinflammatory cytokine secretion and inhibit binding of proinflammatory cytokines to their receptors

References:^[1][2][3]

• A group of signaling proteins that regulate immune response as well as cellular proliferation and differentiation.
• Each group of interleukins acts on a specific group of cells.

- 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:^{[8][9][10][11][12][13][14]}

Interferons ^{[11][12][13][14][15]}

• Interferons are cell signaling glycoproteins that are secreted by cells infected by viruses, bacteria, or parasites, as well as by leukocytes and fibroblasts in response to infection or neoplastic proliferation.
• Have antiviral (RNA as well as DNA viruses); , antimicrobial, and antiproliferative properties
• Are a part of the innate immune system
• Used in the treatment of chronic infections (hepatitis B and C, chronic granulomatous diseases), immune-mediated diseases (multiple sclerosis), and even tumors (leukemia, Kaposi sarcoma) ^[16]

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 ^{[10][11][12][13][14]}

• Pro-inflammatory cytokines secreted by leukocytes in response to inflammation and/or infection
• Their signaling pathways regulate inflammation, apoptosis, and cellular proliferation and differentiation.
• There are over 20 tumor necrosis factors, of which cachectin and lymphotoxin-alpha are the most important.

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.

• A group of regulatory proteins with similar structure and target receptors that are involved in:
  • Cell growth
  • Embryonic development (esp. bone, cartilage, and skeletal muscle)
  • Regulation of the immune system.
• Dysregulation of TGF genes is implicated in the pathogenesis of autoimmune diseases and various types of cancers.

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

Overview

• Eicosanoids are pro-inflammatory and anti-inflammatory autocrine or paracrine cell signaling molecules that are derived from arachidonic acid (ARA).
• Arachidonic acid
  • Is cleaved off the membrane phospholipids by phospholipase A2 (this step is inhibited by corticosteroids)
  • Can be synthesized from linoleic acid; becomes an essential fatty acid in linoleic acid deficiency
  • Can act as a second messenger (for example, in H1 histamine receptor signaling)
• There are four subtypes of eicosanoids:
  • Prostaglandins
  • Prostacyclins
  • Leukotrienes
  • Thromboxane A2

Arachidonic acid pathway

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

• 5-lipoxygenase pathway
  • 5-lipoxygenase breaks down AA to release 5-HPETE (5-hydroperoxyeicosatetraenoic acid).
  • This step is inhibited by zileuton.
• Cyclooxygenase pathway
  • COX-1/COX-2 break down AA to release prostaglandin H₂.
    • COX-1
      • Expressed constitutively in all tissues
      • Predominant isotype in gastric mucosa and renal cells
      • Inhibition increases the risk of gastric ulcers (due to decreased PGE₂ production)
    • COX-2: Expression is induced by proinflammatory cytokines and is highest in the cells affected by inflammation.
  • This step is inhibited by aspirin (irreversible inhibition), other NSAIDs (reversible inhibition), and selective COX-2 inhibitors.

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”

Recombinant cytokines are synthetic analogs of endogenous cytokines used to stimulate specific cells in order to enhance the immune system. ^[41]