CYTOKINES OVERVIEW

Cytokines are low molecular weight (15-25 kDa) and soluble proteins, produced by both immune and non- immune cells, such as leukocytes and endothelial cells, which play fundamental roles for allowing communication between different cell types.

- different cytokines inducing similar effects, redundancy,

- many cell types producing the same cytokine, pleiotropy,

- cytokines have short half-life and act as “autacoids”, i.e. as factors released locally and acting on cells in close proximity to their release, influencing the physiology of the cells in their microenvironmen. this paracrine mode of action of cytokines is often associated to autocrine effects (i.e. the released cytokine interacts with specific receptors on the surface of the secreting cell) frequently aimed at curtailing its effect to the local microenvironment, Overproduction of cytokines (or their therapeutic administration) may exceptionally lead to their systemic dissemination as observed during sepsis,

- cytokines act via specific receptors as well as intracellular signalings, tuning tissue development,

haematopoiesis, inflammation and immune responses [1]. Cytokine receptors add a further level of complexity. Frequently, a single cytokine or chemokine can interact with more than a single receptor on the surface of target cells; receptors are often released from the cells by proteolytic cleavage and act as buffering systems limiting the effect of the cognate cytokine. Some receptors act as “decoys” (for example, type II receptors for interleukin-1, IL-1) by sequestering the cytokine and thus impeding its interaction with functional receptors [2]. Chemokine receptors may accomplish a similar role still remaining expressed at the plasma membrane uncoupled from the transducing elements interacting with their cytoplasmic tails [2],_______________________________________________________________________________________

*Address Correspondence to this Author Dr.

Massimo Alfano (Ed)

All rights reserved - © 2010 Bentham Science Publishers Ltd.

- analogues of cytokines and cytokine receptors are expresses by DNA viruses such as Poxviruses; these virus-encoded molecules favor virus capacity to infect cells by shutting-off inflammatory responses [3].

On the other hand, HIV proteins such as Tat Nef and Vpr, owns cytokine-like characteristics. Indeed, Tat induces the expression and release of cytokines from infected cells or upon being uptake by uninfected neighboring cells. On the other side, HIV accessory proteins Nef and VpR are internalized in infected cells only by virions [4]. Depending on the cell type, receptor engagement (In the case of extracellular Tat), the effect of these viral proteins is variable, but often involves modulation of cytokines or cytokine receptors.

All physiological and pathological processes are tuned by multiple interactions involving cellular phenotypes and soluble factors, also involving the complex network of cytokines and their receptors. Thus, cytokines levels in peripheral circulation are very low [5] but drastically increased in response to pathologies. On the other hand, solube cytokines receptors (sIL-1r, sIL-2r, sIL-6r) can be easily detected in serum or other biological fluids even in healthy individuals [5], likely in order to prevent systemic effects of cytokines thus limiting their action at athe autocrine/paracrine levels.

Cytokines control both innate and specific immune responses, including the on-off state of inflammatory processes [6], and specific immune responses. They can also exert mitogenic activity or promote growth arrest, cell differentiation and, in some case, trigger apoptotic pathways [7]. Cytokines are conventionally subdivided into pro- and anti-inflammatory molecules, whereas some of them exert predominant immunoregolatory effects, for example in terms of polarization towards Th1 (cellular immune response, phagocyte-dependent), Th2 (humoral immune response, phagocyte-independent) [8] and, more recently, T regulatory (Treg) [9] and Th17 inflamamtory cells [10].

Due to their fundamental role in the above processes, chronic dysregulation of cytokines production or action is thought to have a central role in the development of pathological processes, such as autoimmunity [11], tumor development and metastasis, AIDS pathogenesis, as well as. to modulate the expression of multi-drug receptors, such as P-gp [12], thus influencing the bioavailability of drugs.

Cytokines are among the very first molecules released during inflammatory processes, either of bacterial or viral origin, independently of antigen specificity. Acute inflammation represents the first line of defense towards pathogens, and is characterized by a very fast and finely chronologically controlled expression of cytokines. In fact, in the case of bacterial infection inflammatory cytokines are secreted within 4-8 hours (with the production of TNF-α, followed by IL-1 and IL-6) after tissue localization of the pathogen. Inflammatory cytokines produced by resident macrophages enhances endothelial permeability (TNF-α and IL-1), favors recruitment of leukocytes (IL-8 and chemokines) to the site of inflammation, as well as to induce the cytotoxic mechanisms (via IL-12 induced secretion of INF-γ by T cells) of the recruited leukocytes (i.e., neutrophils and monocytes). The release of inflammatory cytokines is then followed by production of anti­inflammatory cytokines, such as IL-4, IL-10, IL-13 and TGF-β, and cytokine decoy receptors.