Cytokines

Introduction

Cytokines are a large and heterogenous group of small extracellular mediators ( Mr between 8-30 kD). Cytokines are not a structurally defined entity and are also called lymphokines, monokines, interleukins, chemokines, interferons, growth factors etc.

Examples of structural and functional groups of cytokines:

    interferons

    (IFN-α, ß, γ)

    hematopoietic cytokines /
    colony-stimulating factors

    (IL-3, IL-5, IL-7, GM-CSF, G-CSF, M-CSF)

    IL-1 family

    (IL-1α IL-1ß, IL-18, IL-1RA)

    TNF family

    (TNF-α, TNF-ß, CD40 ligand, CD95 ligand, TRAIL)

    chemokines

    (IL-8, MIP-1-α, RANTES)

    immunoregulatory cytokines

    (IL-2, IL-4, IL-10, IL-12)

 

Molecular mechanisms of cytokine action:

Receptors

Cytokines bind to several classes of receptors on the plasma membrane with high affinity and specificity. These receptors fall into different classes, those with enzymatic tyrosine kinase activity (e. g. the receptors of certain hematopoietic growth factors (M-CSF, SCF), G-protein-coupled receptors (chemokine receptors) and several groups that bind to other intracellular adaptor proteins (IL-1-, TNF-, interferon- and hematopoietic cytokine receptor families).

Signalling

Ligand-dependent receptor clustering activates several intracellular signalling patwhays. These pathways consist of consecutive interactions between protein components that in part involve enzymatic activities. The activity of many proteins in a given cytokine-activated pathway is regulated by reversible phosphorylation. The NF-κB, the MAP kinase cascades and the JAK/STAT and PI-3 kinase pathways are intensively studied examples. Certain receptors (of the TNF-R family) can activate caspases; a family of proteases that executes programmed cell death. Other protein synthesis-independent effects of cytokines include cytoskeletal changes and modulation of cell surface receptors and adhesion molecules.

Gene expression

Most cytokine-activated intracellular pathways ultimately turn on expression of genes whose products change the biological function of the same or a neighbouring cell. These include cytokines (hence the term “cytokine network“), cell surface receptors and adhesion molecules, enzymes involved in degradative processes (e. g. collagenases) and in formation of small molecular weight mediators (e. g. cyclooxygenase I and II, inducible NO-synthase).

Regulation of cytokine networks

Most cytokines are rapidly induced in response to several groups of external stimuli which include (i) bacterial, viral, fungal and parasite structures that are recognized by members of the Toll-like receptor family, (ii) nonspecific physicochemical stress/cell damage, and, (iii) molecules formed/activated in response to the above stimuli, i.e., released cytokines (e. g. TNF, IL-1), activated complement components and structures of the specific immune system (antibodies, T cell receptors).

The intracellular pathways activated by these stimuli have to enable stringent spatial, temporal and qualitative control of the response, necessitated by the potentially hazardous consequences of unscheduled cytokine activities. Absence of cytokine formation under normal conditions is the consequence of low promoter activity and rapid turnover of the mRNAs. Several thousand fold increases in cytokine formation are achieved within minutes by simultaneous activation of transcription, stabilization of the mRNA and increase in translational efficiency . Several mechanisms restrict the response and let the system return to its basal state: down regulation of receptors, induction of phosphatases that inactivate components of the signalling pathways, etc. Systemically the release of glucocorticoids is a major feedback mechanism that dampens the response at multiple levels.

Examples of gene expression patterns induced by cytokines and cytokine-activation stimuli (e.g. LPS).

Cytokines in Medicine

Knowledge on cytokines has been exploited to improve the therapy of many diseases, basically in two ways:

  1. Application of cytokines as drugs, e.g. recombinant Interferons, human recombinant colony-stimulating factors (GM-CSF, G-CSF), recombinant Interleukin 2, and Erythropoietin.

  2. Extracellular interference with cytokine action, e.g. prevention of interaction of cytokines with their cell surface receptors by soluble receptors (Etanercept), anti-cytokine or -cytokine receptor- antibodies (Infliximab), or natural antagonists (IL-1RA).

  3. Blockade of cytokine synthesis or intracellular action.

Inhibition of cytokine synthesis by drugs.

The immunosuppressants cyclosporine, tacrolimus and sirolimus inhibit T-lymphocyte activation, IL-2 gene expression and IL-2-dependent progression through the cell cycle. Glucocorticoids suppress a large number of proinflammatory cytokines.

An area that is actively explored worldwide is to suppress the intracellular mechanisms of cytokine action. At present for many cytokines the molecular mechanisms of their actions have been worked out and an increasing numbers of compounds is available to suppress cytokine actions pharmacologically.

A number of protein kinase inhibitors of the NFkB, p38, JNK and ERK MAP kinase signalling pathways is currently tested in clinical trials.

However, the overall wanted and unwanted consequences of these strategies, their specificity and their ultimate benefit in humans is still unclear. These questions form the major focus of the SFB566.