Cytokines are soluble (glyco)proteins, nonimmunoglobulin in nature, released by living cells of the host, which act nonenzymatically in picomolar to nanomolar concentrations through specific receptors to regulate host cell function. Cytokines make up the fourth major class of soluble intercellular signaling molecules, alongside neurotransmitters, endocrine hormones, and autacoids. They possess typical hormonal activities:
Target cells, on which cytokines transform their information signal, may be localized in any body compartment (sometimes a long distance from the site of secretion). Other type of these molecules act mostly on neighbouring cells in the microenvironment where they have been released. These are characterized as local hormones and their secretion is brought about by autocrine (only the cell or organ of secretion is affected) or paracrine mechanisms. During the paracrine secretion some cytokines may escape cell binding and may spill over into general circulation via lymph or plasma. This is important, especially for the products of lymphoid cells, which are mobile after having picked up the message in the microenvironment throughout the body and therefore their immunoregulatory products, (lymphokines, monokines, interleukins and other cytokines), despite being of local hormone character, may act in fact systemically.
Cytokines are synthesized, stored and transported by various cell types not only inside of the immune system (lymphokines, interleukins, monokines, tumour necrosis factors, interferons) but also by other cells which are mainly studied in haematology (colony-stimulating factors), oncology (transforming growth factors), and cell biology (peptide growth factors, heat shock and other stress proteins). The main types of cytokines are listed in Table 1.9.
Table 1.9: Main types of cytokines
Lymphokines are cytokines secreted
mainly by activated 
lymphocytes and the term
monokines refers to analogous
immunoregulators produced by activated macrophages and monocytes.
In order to unify the terminology of these factors, the term
interleukin was accepted. Besides the term expressing their
origin, cytokines may be also named according to their function,
as are
interferons, growth and
differentiation factors,
colony-stimulating factors, etc.
The central role of cytokines is to control the direction, amplitude, and duration of immune responses and to control the (re)modeling of tissues, be it developmentally programmed, constitutive, or unscheduled. Unscheduled remodeling is that which accompanies inflammation, infection, wounding, and repair. Individual cytokines can have pleiotropic (multiple), overlaping and sometimes contradictory functions depending on their concentration, the cell type they are acting on, and the presence of other cytokines and mediators. Thus the information which an individual cytokine conveys depend on the pattern of regulators to which a cell is exposed, and not on one single cytokine. It is supposed that all cytokines form the specific system or network of communication signals between cells of the immune system, and between the immune system and other organs. In this inter-cell signalling network, the signal is usually transfered by means of a special set of cytokines.
Because of the potent and profound biological effects of cytokines, it is not surprising that their activities are tighly regulated, most notably at the levels of secretion and receptor expression. Additional regulatory mechanisms are provided by the concomitant action of different cytokines and the presence in biological fluids of specific inhibitory proteins, soluble cytokine-binding factors and specific autoantibodies.
The cytokine system is a very potent force in homeostasis when
activation of the network is local and cytokines act vicinally in
surface-bound or diffusible form, but when cytokine production is
sustained and/or systemic, there is no doubt that cytokines
contribute to the signs, symptoms, and pathology of inflammatory,
infectious, autoimmune, and malignant diseases.
TNF-
is an
excellent example of such dual action. Locally it has important
regulatory and antitumour activities but when
TNF-
circulates in
higher concentrations beyond the organ of origin, it may be
involved in the pathogenesis of endotoxic shock, cachexia and
other serious diseases.
From the point of inflammation view there are two main groups of cytokines: proinflammatory and anti-inflammatory (Table 1.10). Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. Anti-inflammatory cytokines belong to the T cell-derived cytokines and are involved in the down-regulation of inflammatory reactions.
Table 1.10: Cytokines involved in inflammatory reactions
The central role in inflammatory responses have
IL-1 and
TNF-
,
because the administration of their antagonists, such
as IL-1ra (IL-1 receptor antagonist), soluble fragment of IL-1
receptor, or monoclonal antibodies
to TNF-
and soluble TNF
receptor, all block various acute and chronic responses in animal
models of inflammatory diseases. Some of these antagonists are
beginning to utilize as anti-inflammatory agents in diseases such
as sepsis and rheumatoid arthritis. IL-1 and TNF-
together with
IL-6 serve as endogenous pyrogens. The up-regulation of
inflammatory reaction is also performed by IL-11, IFN-
, IFN-
,
and especially by the members of chemokine superfamily. On the
other hand, anti-inflammatory cytokines (IL-4, IL-10, IL-13) are
responsible for the down-regulation of inflammatory responses.
They are able to suppress the production of proinflammatory
cytokines. Their strong anti-inflammatory activity suggest
possible utilization in management of many inflammatory diseases,
including sepsis, rheumatoid arthritis, inflammatory bowel
disease, psoriasis, T cell-mediated autoimmune diseases such as
type I diabetes, as well as in acute graft-versus-host disease.
IL-10 is capable of effectively protecting mice from
endotoxin-induced shock, a lethal inflammatory reaction mediated
by TNF-
and IL-1. The production of most lymphokines and
monokines such as IL-1, IL-6 and TNF-
is also inhibited by
transforming growth factor 
(TGF-
).
But, on the other hand,
TGF-
has a number of proinflammatory activities including
chemoattractant effects on neutrophils, T lymphocytes, and
unactivated monocytes. TGF-
has been demonstrated to have in
vivo immunosupressive and anti-inflammatory effects as well as
proinflammatory and selected immunoenhacing activities. When
administered systemically, TGF-
acts as an inhibitor, but if
given locally can promote inflammation.
Generally, TGF-
stimulates neovascularization and the proliferation and activities
of connective tissue cells and is a pivotal factor in scar
formation and wound healing. But TGF-
has antiproliferative
effects on most other cell types including epithelial cells,
endothelial cells, smooth muscle cells, fetal hepatocytes, and
myeloid, erythroid, and lymphoid cells. TGF-
is a potent
immunosupressive cytokine that supresses cell-mediated as well as
humoral immunity (including tumour immunity).