Cytokines

Introduction

The term cytokine is a generic name for the soluble molecules that mediate reactions between cells, acting via specific receptors on those cells. They are particularly important during effector stages of the immune system and the development of haematopoietic cells

Nomenclature and classification

Nomenclature of the cytokines was first based on their activity both in vivo and in vitro, with the name being abbreviated to acronyms. For example, when a factor isolated from antigen-activated lymphocytes was added to non-immune peritoneal macrophages, their migration from capillary tubes was inhibited. This led to the factor being named migration inhibition factor, or MIF for short. It was then discovered that many biological functions were being produced by the same chemicals, which led to the classification of cytokines based on either the cell populations that secrete them or their function:

• Monokines- produced by myeloid cells (macrophages, monocytes)
• Lymphokines- produced primarily by lymphocytes
• Interleukins- produced by leukocytes in general
• Chemokines- directing cell migration, activating cells in response to infectious agents/tissue damage
• Interferons- produced by many different cells in response to viral infection

Common cytokines and nomenclature

Name	Abbreviation	Examples
interleukins	IL	IL-1, IL-2
interferons	IFN	IFN-alpha
tumour necrosis factors	TNF	TNF-alpha
growth factors	GF	NGF, EGF
colony stimulating factors	CSF	M-CSF, G-CSF
chemokines	-	RANTES, MCP-1

Functions of cytokines

Mediating and regulating innate immunity: bacterial and viral products, such as LPS, stimulate macrophages and natural killer cells to secrete cytokines that primarily act on endothelial cells and leukocytes. They stimulate the early stages of the inflammatory reaction to microbes.

Mediating and regulating adaptive immunity: in response to specific recognition by T lymphocytes, cytokines are produced that have a wide range of functions, including:

• regulating the growth and differentiation of some lymphocyte populations
• recruitment, activation and regulation of specialised effector cells, e.g. mononuclear phagocytes, neutrophils, eosinophils

Stimulating haematopoiesis: produced primarily by bone marrow stromal cells and leukocytes, these cytokines stimulate the growth and differentiation of immature leukocytes. By binding onto specific receptors on cell membranes, cytokines are able to exert their actions by triggering signal-cascade mechanisms that ultimately result in altered gene expression. Cytokines have an incredibly high affnity for their receptors, and are therefore able to act at picomolar concentrations. Cytokines can exert antagonistic effects on each other.

Important cytokines

Cytokines primarily produced by macrophages:

• GM-CSF (granulocyte macrophage colony stimulating factor)- stimulates growth and differentiation of granulocytes, macrophages, neutrophils and eosinophils
• IL-1- stimulates Th2 cells and acute phase response
• IL-6- stimulates growth and differentiation of B and T cells and acute phase response
• IL-12- stimulates Th1 cells
• IL-18- stimulates IFN-gamma production by T cells and NK cells, favours Th1 response
• TNF-α- stimulates local inflammation and endothelial activation

Cytokines primarily produced by Th1 cells:

• IL-2- stimulates proliferation and differentiation of T cells, activates NK cells and macrophages
• IFN-γ- activates macrophages, increases expression of MHC I and II molecules, increases antigen presentation
• TNF-β- stimlulates killing mechanisms in T and B cells and endothelial activation

Cytokines primarily produced by Th2 cells:

• IL-4- activates B cells and IgE switch, supresses Th1 cells
• IL-5- stimulates eosinophil growth and differentiation
• IL-10- suppresses macrophage functions

Although neutrophils produce a lower amount of cytokines per cell than other immune cell types, they are often the first and most common cell type present at sites of infection. This makes them a physiologically important source of cytokines, such as IL-12.

Chemokines

The chemokines are a superfamily of cytokines, all related in terms of sequence and gene structure. The family is also known as the 'small cytokine' family (scy) or the intercrines. All have a relatively small molecular weight of ~5-10kDa and can be divided in one of two groups based on the position of the cystein residues (important for the tertiary structure):

• C-C subgroup- cysteine residues are adjacent to each other. Important members include:
  • Interleukin 8
  • MGSA- melanoma growth stimulatory activity
  • PF4- platelet factor 4
  • βTG- β-thromboglobulin
• C-X-C subgroup- residues are separated by another amino acid. Important members include:
  • MCAF- macrophage chemotactic and activating factor
  • RANTES
  • LD-8
  • ACT-2

Chemokines are released by many cell types, and are present in the earliest phase of infection, with actions including the following:

• Lymphoid trafficking
• Wound healing
• Th1/Th2 development
• Angiogenesis/angiostasis
• Lymphoid organ development
• Inflammation
• Cell recruitment

Cytokines in pathology

Bacterial septic shock

This is the overproduction of cytokines developing a few hours after infection by certain Gram-negative bacteria, including:

• E. coli
• K. pneumoniae
• P. aeruginosa
• E. aerogenes

Bacterial cell wall endotoxins are the cause of septic shock, stimulating macrophages to release IL-1 and TNF-α at excessive levels. The condition is often fatal and symptoms include a sudden drop in blood pressure, fever, diarrhoea and blood-clotting in multiple organs.

Bacterial toxic shock

This condition is caused by bacterial toxins known as superantigens (antigens that bind simultaneously to MHC II and the beta-V domain of the T cell receptor) that activate large numbers of T cells despite specificity. A number of bacteria have been implicated in the production of superantigens, including:

• S. aureus- produces enterotoxins and toxic-shock syndrome toxin
• M. arthritidis

The large number of T cells activated by such toxins (between 5-25% of all T cells, compared to less than 0.01% activated towards conventional antigens) means an excessive amount of cytokines produced, such as IL-1 and TNF. These elevated amounts cause the same systemic reactions as seen in bacterial septic shock.

Lymphoid and myeloid cancers

The excessive production of cytokines has been linked to some types of cancer, e.g. IL-6 has been shown to be secreted by myeloma cells, plasmacytoma cells and cervical and bladder cancer cells. IL-6 is known to act in an autocrine manner to stimulate cell proliferation.