Cytokines
15.8.4 Cytokines
- … some viruses subvert the immune response by
- producing homologs of mammalian cytokines or
- their receptors.
- J. J. Oppenheim and M. Feldmann20(p7)
Cytokines are proteins or glycoproteins produced after stimulation (such as activation of immune cells) that act at short distances in very low concentrations to produce various effects, such as immune and inflammatory reactions, repair processes, and cell growth and differentiation.6,20-25 Each cytokine has multiple effects and overlaps with other cytokines, including structurally dissimilar ones, in those effects. The multiple effects (pleiotropy) are explained by the presence of cytokine receptors on a wide variety of cells, and the overlap (redundancy) by structural similarities of the intracellular portions of cytokine receptors.26
Cytokines were originally named by function. Because of their multiple and overlapping functions,20 the interleukin nomenclature27,28 was proposed to simplify terminology of this major class of cytokines and, it was hoped, subsequent regulatory immune system proteins. The more recent grouping of cytokines by receptor families and signaling pathways, however, does not necessarily correspond to previous groupings; eg, the interleukins fall into more than one family.
Cytokine Families and Subfamilies.
Molecular similarity of cytokine receptors has resulted in their grouping into families and subfamilies26:
chemokine families (see 15.8.1, Chemokines)
interleukin 1/toll-like receptors (IL-1/TLR)
platelet-derived growth factor family (PDGF)
receptor tyrosine kinases
transforming growth factor β (TGF-β) receptor serine kinase family
tumor necrosis factor (TNF)
type 1 (hematopoietins)
βc-utilizing (common cytokine receptor β chain)
γc-utilizing (common cytokine receptor γ chain)
gp130-utilizing
heterodimeric
homodimeric
type 2 (interferons; IL-10 family receptors)
heterodimeric
Cytokine signaling pathways are associated with the families and subfamilies.
Cytokine Signaling Pathways |
Expansion or Origin of Term |
Associated Cytokine Family |
|---|---|---|
caspases |
TNF |
|
FADD |
Fas-associated death domain |
TNF |
FAST-1 |
forkhead activin signal transducer |
TGF-β receptor serine kinase family |
IRAK |
IL-1 receptor-associated kinase |
IL-1/TLR |
Jak1 |
Janus kinase 1 |
type 1 |
Jak2 |
Janus kinase 2 |
type 1 |
Jak3 |
Janus kinase 3 |
type 1 |
MyD88 |
myeloid differentiation marker |
IL-1/TLR |
NF-κB |
nuclear factor–κB |
IL-1/TLR |
Ras/Raf/MAPK |
ras protein, raf protein (see also 15.6.3, Oncogenes and Tumor Suppressor Genes), mitogen-activated protein kinases |
type 1, receptor tyrosine kinases |
SARA |
SMAD anchor for receptor activation |
TGF-β receptor serine kinase family |
SMADs |
mothers against decapentaplegic (dpp) signaling (MAD) in Drosophila and Sma genes from Caenorhabditis elegans29 |
TGF-β receptor serine kinase family |
STAT1 |
signal transducer and activator of transcription 1 |
type 1 |
STAT2 |
type 1 |
|
STAT3 |
type 1 |
|
STAT4 |
type 1 |
|
STAT5 |
type 1 |
|
STAT5a |
type 1 |
|
STAT5b |
type 1 |
|
STAT6 |
type 1 |
|
TAK1 |
TGF-β–associated kinase |
TGF-β receptor serine kinase family |
TRADD |
TNF receptor–associated death domain |
TNF |
TRAFs |
TNF-α receptor–associated factors |
TNF |
TRAF6 |
IL-1/TLR |
|
Tyk2 |
tyrosine kinase 2 |
type 1 |
The pathway terms need not be expanded, but context should be clear at first mention, eg:
the Jak1 signaling pathway
Colony-Stimulating Factors.
Colony-stimulating factors (CSFs) stimulate growth and differentiation of 1 or more blood cell types (neutrophils, eosinophils, monocytes/macrophages). Terms often include the letters SF, but not always (eg, interleukins 3, 4, and 5—IL-3, IL-4, IL-5—which are also CSFs). Expand CSF terms at first mention:
granulocyte-macrophage colony-stimulating factor |
GM-CSF |
granulocyte colony-stimulating factor |
G-CSF |
macrophage colony-stimulating factor |
M-CSF |
Hormones.
These hormones are also considered cytokines:
erythropoietin |
Epo |
growth hormone |
GH |
leptin |
|
prolactin |
PrL |
thrombopoietin |
Tpo |
Interleukins.
A subset of cytokines were designated as interleukins in 1978 for “their ability to act as communication signals between different populations of leukocytes.”27(p2929) The interleukins have other biological effects as well. Their nomenclature was formalized in 1991.28 They are designated by number in order of discovery, eg, interleukin 1, interleukin 18, interleukin 29, but in general have no structural or functional relationship to one another. Although most have now been recognized as members of larger cytokine families, they retain their original designations. Specific interleukins are mentioned most commonly in their abbreviated form (note hyphen):
IL-1
IL-18
IL-29
The IL-1 family includes 2 forms of IL-1:
IL-1α
IL-1β
and the IL-1 receptor antagonist:
IL-1ra
Receptors for interleukins are designated, at minimum, with the interleukin name plus a capital R, eg:
IL-2R
IL-4R
Receptor names designating subtypes may be even more specific:
IL-1RI
IL-1RII
Greek letters are used for subunits (chains) of the same receptor:
IL-2Rα |
IL-2Rβ |
IL-6Rα |
IL-6Rβ |
IL-12Rβ1 |
IL-12Rβ2 |
Terms for interleukins from different species should be expanded at first mention:
human IL-2 |
hIL-2 |
mouse IL-4 |
mIL-4 |
viral IL-10 |
vIL-10 |
For terminology for therapeutic interleukins, see 15.4.13, Drugs, Nomenclature for Biological Products.
Interferons.
Interferons (IFNs) are another group of cytokines, originally discovered (and named) because of their interference with viral replication.
The type I IFNs, also known as antiviral interferons, are as follows:
IFN-α
IFN-β
IFN-λ1 (IL-29)
IFN-λ2 (IL-28A)
IFN-λ (IL-28B)
IFN-κ
IFN-ω
IFN-τ
Type II IFN, also known as immune interferon, is
IFN-γ
For terminology for therapeutic interferons, see 15.4.13, Drugs, Nomenclature for Biological Products.
Other Cytokines.
Other cytokines include the following:
Term |
Abbreviation |
|---|---|
cardiotrophin 1 |
CT-1 |
ciliary neurotrophic factor |
CNTF |
endothelial growth factor |
EGF |
FLT-3/FLT-2 ligand |
FL |
high mobility group box chromosomal protein 1 |
HMGB-1 |
leukemia inhibitory factor |
LIF |
lymphotoxin α |
LTα |
oncostatin M |
OSM |
receptor activated nuclear factor–κB ligand |
RANKL |
stem cell factor |
SCF, c-kit ligand |
transforming growth factor β |
TGF-β, TGF-β1, TGF-β2, TGF-β3 |
tumor necrosis factor α |
TNF-α |
tumor necrosis factor β |
TNF-β |