Cytokines are biologically active substances secreted by mono-cytes, lymphocytes, and other cells and are actively involved in innate immunity, adoptive immunity, and inflammation. They actively take part in a wide range of biological activities varying from chemotaxis to activation of specific cells.
Cytokines were initially identified as products of immune cells that act as mediators and regulators of immune processes. Many cytokines are now known to be produced by cells other than immune cells, and they can have effects on nonimmune cells as well. Cytokines are currently being used clinically as bio-logical response modifiers for the treatment of various disorders.
Cytokines are not typically stored as preformed proteins. Rather their synthesis is initiated by gene transcription and their mRNAs are short-lived. They are produced as needed in immune responses. Many individual cytokines are produced by many cell types and act on many cell types (i.e., they are pleiotropic), and in many cases cytokines have similar actions (i.e., they are redun-dant). Redundancy is due to the nature of the cytokine receptors.
Cytokines can be grouped into different categories based on their functions or their source, but it is noteworthy that because they can be produced by many different cells and act on many dif-ferent cells (Table 17-1), any attempt to categorize them will be subject to limitations. Cytokines may be categorized as follows:
a) Mediators affecting lymphocytes.
b) Mediators affecting macrophages and monocytes.
c) Mediators affecting polymorphonuclear leukocytes.
d) Mediators affecting stem cells.
e) Mediators produced by macrophages that affect other cells.
Interleukin-1 (IL-1): It is a protein produced mainly by activatedmacrophages and monocytes. Its production is stimulated by antigens, toxins, and inflammatory processes but inhibited by cyclosporine and corticosteroids. It is an important interleukin, which mediates a wide range of metabolic, physiological, inflammatory, and hematological activities. It has many important functions, which are given below:
· It activates a wide range of target cells including T and B lymphocytes, neutrophils, epithelial cells, and fibroblasts to proliferate, differentiate, or synthesize specific products. For example, it stimulates helper T cells to produce IL-2, and stimulates B cells to proliferate and synthesize antibodies, etc.
· It acts on the hypothalamus to cause fever associated with infections and other inflammatory reactions.
Interleukin-2 (IL-2): IL-2 is a protein produced mainly byhelper T cells. It is a major T-cell growth factor. It stimulates both helper and cytotoxic T cells to grow. It also promotes the growth of B cells and can activate natural killer (NK) cells and monocytes.
IL-2 acts on T cells in an autocrine fashion. Activation of T cells results in expression of IL-2R and the production of IL-2. The IL-2 binds to the IL-R and promotes cell division. When the T cells are no longer being stimulated by antigen, the IL-2R will eventually decay and the proliferative phase ends.
Interleukin-4 (IL-4): It is a protein produced mainly by helperT cells and macrophages. It stimulates the development of Th-2 cells, the subset of helper T cells that produces IL-4 and IL-5 and enhances humoral immunity by producing antibodies. It is also required for class (isotype) switching from one class of antibodies to another within antibody-producing cells.
Interleukin-5 (IL-5): It is a protein produced by helper T cells.It promotes the growth and differentiation of B cells and eosinophils. It enhances the synthesis of IgA and also stimulates the production and activation of eosinophils.
Interleukin-6 (IL-6): It is a protein produced by helper T cells andmacrophages. It stimulates the production of acute phase proteins by the liver. It also acts on the hypothalamus to cause fever.
Other interleukins: IL-10, IL-12, and IL-13 are the otherinterleukins that affect lymphocytes. IL-10 is produced by activated macrophages and Th-2 cells. It is predominantly an inhibitory cytokine. It inhibits production of type I interferon. It inhibits production of interferon-gamma by Th-1 cells, which shifts immune responses toward a Th-2 type. It also inhibits cytokine production by activated macrophages and the expression of class II MHC and costimulatory molecules on macrophages, resulting in a depression of immune responses.
IL-12 is produced by activated macrophages and dendritic cells. It stimulates the production of interferon-gamma and induces the differentiation of Th cells to become Th-1 cells. In addition, it enhances the cytolytic functions of Tc and NK cells.
IL-13 is produced by Th-2 cells. It is associated with patho-genesis of allergic airway disease (asthma). It is involved in the occurrence of hyper-responsiveness seen in asthma.
Transforming growth factor-beta (TGF-b): It is produced byT cells and many other cell types. It is primarily an inhibitory cytokine. It inhibits the proliferation of T cells and the activation of macrophages. It also acts on polymorphonuclear leukocytes and endothelial cells to block the effects of proinflammatory cytokines. In essence, it suppresses the immune response when it is not required after an infection, and thereby it promotes the healing process.
Chemokines are a subtype of cytokines of low molecular weight and with a characteristic structural pattern. More than 50 che-mokines varying in size from 68 to 120 amino acids have been identified. The alpha-chemokines, such as IL-8 are produced by activated mononuclear cells, which attract neutrophils. The beta-chemokines, such as RANTES (regulated upon activation, normal T-cell expressed and secreted) and MCAF (monocyte chemotactic and activating factor), are produced by activated T cells and attract macrophages and monocytes.
Chemokines are produced by endothelial cells, resi-dent macrophages and various cells present at the site of infection:
They attract either macrophages or neutrophils to the site of infection, hence are involved in chemical-induced migration of leukocytes—a process called chemotaxis. Specific recep-tors for chemokines are present on the surface of monocytes and neutrophils.
They also facilitate migration of white cells into the tissue to reach the infected area. They do so by activating integrins on the surface of neutrophils and macrophages that bind to the intercellular adhesion molecule (ICAM) proteins on the surface of the endothelium.
Tumor necrosis factor (TNF-a): It is produced by activatedmacrophages in response to microbes, especially the lipopolysaccharide of Gram-negative bacteria. It is an important mediator of acute inflammation. It mediates the recruitment of neutrophils and macrophages to sites of infection by stimulating endothelial cells to produce adhesion molecules. It also produces chemokines, which are chemotactic cytokines. TNF-a also acts on the hypothalamus to produce fever, and it promotes the production of acute phase proteins.
Chemokines and other chemotactic factors: Chemokinesand other chemotactic factors attract selectively neutrophils, basophils, and eosinophils to the site of infection. For example, IL-8 and C5a component of the complement attract specifically neutrophils.
Leukocyte-inhibiting factor: It inhibits migration of neutro-phils, thereby retaining the cells at the site of infection.
Mediators affecting stem cells include (a) IL-3, (b) granulo-cyte macrophage colony-stimulating factor (GM-CSF), and (c) granulocyte colony-stimulating factor (G-CSF).
· IL-3 produced by helper T cells suppresses the growth and differentiation of bone marrow stem cells.
· GM-CSF produced by macrophages and T lymphocytes stimulates the growth of granulocytes.
· G-CSF is produced by macrophages, fibroblasts, and endo-thelial cells. It facilitates development of neutrophils from stem cells, and hence used to prevent infection in patients receiving cancer chemotherapy.
Tumor necrosis factor (TNF-a): TNF-a, as the name suggests,causes death and necrosis of certain tumor cells in experimental animals. It is also called cachectin because it inhibits lipoprotein lipase in adipose tissues, thereby reducing the utilization of fatty acids, leading to cachexia. TNF-a performs many functions:
· It activates respiratory burst within neutrophils, thereby enhancing killing activities of phagocytes.
· It facilitates adhesion of neutrophils to endothelial cells of blood vessels.
· It also stimulates growth of B cells and increases synthesis of lymphokines by helper T cells.
Macrophage migration inhibition factor (MIF): It is producedby macrophages in response to action by endotoxin. It retains the macrophages at the site of infection. It plays an important role in the induction of septic shock.
Nitric oxide (NO): It is produced by macrophages in response to action by endotoxin. NO causes vasodilatation, thereby inducing hypotension in septic shock.