Cytokines: Immune Response and Inflammation

Cytokines: Definition and General Properties

• Cytokines are low molecular weight soluble proteins produced in response to antigens, acting as intercellular signals to mediate and regulate immune inflammatory responses.
• Cytokine secretion is a self-limited event (transient).
• One cell can secrete more than one cytokine, and one cytokine can affect more than one cell.
• Many cells can secrete the same cytokine.
• Cytokine function can be targeted at:
  • The cells that secrete them (autocrine action)
  • Local cells (paracrine action)
  • Distant cells (endocrine action)

Important Cytokines and Their Main Activities

IL-1

• Produced mainly by macrophages.
• Acts as an inflammatory mediator in innate immunity, recruiting and activating macrophages and neutrophils at the site of infection.
• Stimulates the hypothalamus, inducing fever (endogenous pyrogen).

IL-2

• Produced mainly by activated Th1 cells.
• Stimulates the proliferation of Th cells and increases cytokine secretion.
• Stimulates the proliferation of B cells and antibody secretion.
• Activates Tc cells and macrophages.

IL-4 and IL-5

• Produced by Th2 cells.
• Promote the growth and differentiation of B cells (B cell growth and differentiation factors).
• IL-4 enhances the synthesis of IgE.

Interleukins

• IL-6:
  • Enhances the synthesis of IgA.
  • Produced by macrophages.
  • Stimulates the production of acute phase proteins by the liver.
  • Stimulates the production of neutrophils from bone marrow progenitors.
  • Stimulates B cell growth and differentiation.
  • Attracts leukocytes to the target site (chemotaxis) and hence is called a chemokine.
• IL-12:
  • Produced mainly by Tregs and macrophages.
  • Inhibits the production of IL-12, INF-y, and Th1 cells (down-regulates innate SCM).
  • Activates NK cells and influences T lymphocytes differentiation.
  • Stimulates the activation and recruitment of macrophages and recruits them to the site of infection.
  • Increases the killing power of phagocytes to tumor cells.

Interferons

• Interferons are a large family of proteins secreted by most cells of the body.
• Type 1 interferon (IFN alpha) is produced by leukocytes, while IFN beta is produced by fibroblasts, both having antiviral activity.
• Type 1 interferon (IFN gamma) is produced by Th-1 cells, macrophages, and NK cells.

Complement System

• Complement is a complex system of proteins named C1, C2, C3, etc. in the plasma.
• Complement activation occurs in the presence of a pathogen.
• The complement system activates the pathway to produce opsonins and chemotactic factors.
• During activation, a larger protein is designated as an enzyme, and the smaller proteins are chemotactic factors, helping in contacting the pathogen.
• Activation is initially triggered by the complement system.
• The recognition molecule attached to the pathogen activates the complement system.
• C1 is activated, and activated C1 cleaves C2 and C4.
• Then C3, C5 binds to the pathogen to form an attack complex (C5 convertase).
• The attack complex, C5 convertase, breaks down C5.
• The breakdown product of C5, C5a, is a chemotactic factor and activates mast cells, releasing histamine, which further recruits immune cells to the site of infection.
• The attack complex is formed in all cases of infections.
• C5b, C6, C7, C8, C9 bind to the surface of the pathogen and create pores in the cell wall.
• The properdin system bypasses the classical pathway and leads to the formation of membrane attack complexes.
• The lectin pathway is produced by the liver and activates the complement system by binding to pathogen surfaces that trigger complement activation.