Cytokine Network

These cells have distinct roles in the immune system and communicate with other immune cells by cytokines, which control proliferation, differentiation and function of cells of the immune system. Furthermore, they are involved in processes of inflammation and in the neuronal, hematopoietic and embryonal development of an organism. Unlike hormones, cytokines are not stored in glands as pre-formed molecules, but are rapidly synthesized and secreted by different cells mostly after stimulation. Cytokines are pleiotropic in their biological activities and play pivotal roles in a variety of responses, including the immune response, hematopoiesis, neurogenesis, embryogenesis, and oncogenesis. They frequently affect the action of other cytokines in an additive, synergistic or antagonistic manner (Ref. 1).

Cytokines have been classified on the basis of their biological responses into pro- or anti-inflammatory cytokines, depending on their effects on immunocytes (Ref. 2). Cytokines act in networks or cascades. Major cytokines include:

• Interleukins (IL)
• Growth Hormone
• Interferons (IFN)
• Tumor Necrosis Factors-Alpha and Beta (TNF)

Many of the cytokines act locally like autocrine hormones and their targets are cells of the same or similar type as the cytokine-producing cell.

A characteristic that significantly differentiates some of the cytokines from hormones is the coupling of their activity to cell-cell interactions. The function of some cytokines such IL-1, IL-2, IL-4, IL-5, IL-6 and IL-10 is closely associated with the interactions between B-cells and T-cells (Ref. 3).

• IL-1 activates antigen presenting cells and CD4+ lymphocytes; affects the differentiation of the B-cells and T-cells and other immunocompetent cells and takes part in the regulation of production of other cytokines and GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) (Ref. 6).
• IL-2 stimulates the proliferation and activation of B-cells and T-cells. IL-4 plays a role in the differentiation of TH2 (T Helper Type-2), in allergic responses, and in the switching of antibody types.
• IL-5 stimulates the production and maturation of eosinophils during inflammation.
• IL-8 acts as a chemotactic factor that attracts neutrophils, basophils and T-cells to sites of inflammation.
• IL-12 is a critical linker between the innate immunity and adaptive immunity, capable of TH1 (T Helper Type-1) differentiation and IFN-Gamma release by T-cells and NK cells (Ref. 4).
• IL-10 acts to repress secretion of pro-inflammatory cytokines.
• IL-3 is a potent activator of hemopoietic cells. It stimulates NK cells and acts as a synergist with IL-4 during the induction of CD4+ lymphocyte activation process.
• IL-7 is known as the growth factor of the immature B-cells and T-cells. It induces apoptosis of tumor cells and causes differentiation of cells from a subgroup of acute myeloblastic leukemia.
• IL-9 stimulates the excretion of IL-2, IL-4, IL-6, IL-11, and takes part in a stimulation of cytotoxicity of T-killers and NK cells, inducing apoptosis.
• IL-11 is a pro-inflammative factor, which regulates the functions of B-cells and T-cells. It also takes part in the induction of various killer cell activities and acts as an autocrine factor for the proliferation of megacaryocytes.
• IL-13 is very sensitive to monocytes and B-cells. IL-13 does not act on T-cells but inhibits the proliferation of leukemic pro-B-cells.
• IL-14 is a BCGF (B-Cell Growth Factor) and the hyper production of this interleukin enables the progression of NHL-B (B-cell Type Non Hodgkin's lymphoma).
• IL-15 is analogous to IL-2 and increases the anti-tumor activities of T-killers and NK cells, and the production of cytokines CD4+ lymphocytes.
• IL-17 is principally produced by CD4+ T-cells, which induces granulopoiesis via GMCSF. It takes part in the regulation of many cytokines and can reinforce the antibody-dependent tumor cell destruction.
• IL-18 acts as a synergist with IL-12, especially in the induction of IFN-Gamma production and inhibition of angiogenesis.
• IL-19 is produced mainly by monocytes and is similar to IL-10 in its function. It is stimulated by GM-CSF and regulates the functions of macrophages, and also suppresses the activities of TH1 and TH2.
• IL-21 executes an important role in the regulation of hematopoiesis and immune response. It promotes a high production of T-cells, fast growth and maturation of NK cell and B-cell populations.
• IL-22 is produced by activated T-cells in acute inflammation. It is similar to IL-10 in function, but does not prohibit the production of pro-inflammatory cytokines through monocytes.

In addition to the above cytokines, the release of other inflammatory cytokines, particularly TNFs (TNF-alpha and TNF-beta) from mast cells and the associated recruitment of neutrophils are an important component of the protective action of mast cells against infestation. The secretion of TNF-alpha and TNF-beta by TH1 cells activates macrophages, inhibits apoptosis of neutrophils and eosinophils, and induces vascular endothelial cells at the sites of infection to change the adhesion molecules they express so phagocytes circulating in the blood can bind to them. IFN-alpha, IFN-beta and IFN-gamma are produced in the area of infection during the early phase of immune response. IFN-alpha and IFN-beta induce proliferation of NK cells and stimulate innate and adaptive immune responses that are specifically targeted to virus infections. Upon activation, NK cells release IFN-gamma, which activates macrophages to secrete cytokines that help to activate T-cells and promote the initiation of T-cell responses (Ref. 6).

Cytokines play an important role in the communication between cells of multicellular organisms. As intercellular mediators, they regulate survival, growth, differentiation and effector functions of cells. Besides their pleiotropic effects, cytokine actions are often redundant and they exert their actions, which can be auto-, para- or endocrine, via specific cell surface receptors on their target cells (Ref. 2). They are key players in the regulation of the immune response, particularly during infections, inflammatory joint, kidney, vessel and bowel diseases, or neurological and endocrinological autoimmune diseases (Ref. 5).