Cytokines/immunocytokines, were initially used to separate the immunomodulatory proteins, also called immunotransmitters, from other growth factors that modulate proliferation and bioactivities of non-immune cells. Some cytokines are produced by a rather limited number of different cell types while others are produced by almost the entire spectrum of known cell types.
Recombinant cytokines are in clinical use, and continues attempts are made to develop hybrid molecules from cytokines. 1 must be aware of the fact that current knowledge is still limited. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions, and may show activities that often go beyond the single highly specific property that it is hoped they possess. New factors are being discovered constantly and they extend our knowledge about the Cytokine network.
The understanding of the biological mechanisms governing cytokine actions are an important contribution to medical knowledge. The biochemistry and molecular biology of cytokine actions explain some well-known and sometimes also some of the more obscure clinical aspects of diseases. Knowledge that cytokines create regulatory hierarchies and provide independent and/or interrelated regulatory mechanisms that can confer distinct and interactive developmental functions lays a solid, albeit rather complicated foundation, for current and future clinical experiences.
The concept of "1 producer cell - 1 cytokine - 1 target cell" has been falsified for practically every cytokine investigated more closely. To classify these factors based on their producer or target cells is therefore also problematic.
Classifications based upon identical or shared biological activities of cytokines especially with broad definitions is also problematic for example: BCDF (B-cell differentiation factors), BCGF (B-cell growth factors), Motogenic cytokines, Chemotactic cytokines (Chemokines), CSF (colony stimulating factors), angiogenesis factors, or TRF (T-cell replacing factors). Designations such as HBGF group (heparin binding growth factors) take into account biochemical shared properties by a variety of cytokines which also problematic.
The term cytokine is used today as a generic name for a diverse group which includes proteins and peptides that act in nano-picomolar concentrations as humoral regulators and modulate the functional activities of individual cells & tissues. Cytokines also mediate interactions between cells & regulate processes taking place in the extracellular environment. Many growth factors and cytokines act as cellular survival factors by preventing programmed cell death.
Cytokines resemble hormones in their biological activity & systemic level, for example, inflammation, systemic inflammatory response syndrome, acute phase reaction, wound healing, and the neuroimmune network.
Cytokines act on a wider spectrum of target cells than hormones. The major feature distinguishing cytokines from hormones is the fact that cytokines are not produced by specialized cells organized in specialized glands. Cytokines are secreted proteins which means that their expression sites does not predict where they exert their biological function.
Several cytokines primary structure was found to be identical with enzymes. Cytokines do not possess enzymatic activities although there is a growing list of exceptions. Other cytokines require proteolytic activation.
Cytokines include Interleukins, Lymphokines, Monokines, Interferons (IFN), colony stimulating factors (CSF), Chemokines and a variety of other proteins.
Type-1 cytokines are cytokines produced by Th1 T-helper cells while Type-2 cytokines are those produced by Th2 T-helper cells. Type-1 cytokines include IL-2 (IL2), IFN-gamma (IFN-G), IL-12 (IL12) & TNF-beta (TNF-b), while Type 2 cytokines include IL-4 (IL4), IL-5 (IL5), IL-6 (IL6), IL-10(IL10), and IL-13 (IL13).
Comparison of cytokine sequences shows that primate cytokines (non-human) are closely related. An example: IL-1 alpha (IL1a), IL-1 beta (IL1b), IL-2 (IL2), IL-4 (IL4), IL-5 (IL5), IL-6 (IL6) , IL8 (IL-8), IL-10 (IL10), IL-12 (IL12), IL-15 (IL15), IFN-alpha (IFNA), IFN-gamma (IFN-G), and TNF-alpha (TNFA) which share 93% to 99 % homology at the protein & nucleic acid level with the human sequences.
Cytokines can also be classified into family groups according to the types of secondary and tertiary structure. An example: IL-6 (IL6), IL-11 (IL11), CNTF (C-NTF), LIF, OSM (Oncostatin-M), EPO (Erythropoietin), G-CSF (GCSF), GH (Growth Hormone), PRL (Prolactin), IL-10 (IL10), IFN-alpha (IFN-A), IFN-beta (IFN-B) form long chain 4 helix bundles. IL-2 (IL2), IL-4 (IL4), IL-7 (IL7), IL-9 (IL9), IL-13 (IL13), IL-3 (IL3), IL-5 (IL5), GM-CSF (GMCSF), M-CSF (MCSF), SCF, IFN-gamma (IFNG) form short chain 4 helix bundles. Beta-trefoil structures are formed by IL1-alpha (IL1A), IL1-beta (IL1B), aFGF (FGF-acidic), bFGF (FGF-basic), INT-2 (INT2), KGF (FGF7). EGF, TGF-alpha (TGF-A), Betacellulin (BTC), SCDGF, Amphiregulin, HB-EGF, form EGF-like antiparallel beta-sheets.
Many cytokines are secreted by cells using secretory pathways and therefore are considered glycoproteins. Most genes encoding cytokines give rise to variety of cytokines by means of alternative splicing, yielding molecules with slightly different but biologically significant bioactivities. Usually the expression patterns of different forms of cytokines or of members of a cytokine family are overlapping only partially, suggesting a specific role for each factor.
Membrane-bound cytokines have been are associated with the extracellular matrix. The switching between soluble and membrane forms of cytokines is an important regulatory event. In some cases membrane forms of a cytokine have been found to be indispensable for normal development, with soluble forms being unable to entirely substitute for them.
Numerous cytokines are not stored inside cells though TGF-beta (TGF-b) and PDGF (P-DGF) are stored in platelets or TNF-alpha (TNF-A) and IL-8 (IL8) are found in human skin mast cells. Most of the cytokine’s expression is regulated tightly at practically all levels. The factors are usually produced only by cells after cell activation in response to an induction signal. The production and secretion of cytokines and growth factors frequently is context dependent, i.e., their expression is influenced by individual signals received but also by the balance of signals received through one or more receptors (which themselves may be subject to inducible/repressible expression).
Cytokine’s expression is regulated at the transcription level, translation level, and protein synthesis. The expression of cytokines also seems to be regulated differentially, depending on cell type and developmental age. Secretion or release from the producer cells is a regulated process. Once released, their behavior in the circulation may be regulated by soluble receptors and specific or unspecific binding proteins. Regulation also is at work at the receptor level on target cells and at the level of signaling pathways governing alterations in the behavior of responder cells.
Numerous cytokines are pleiotropic effectors showing multiple biological activities. Multiple cytokines have overlapping activities therefore a single cell frequently interacts with multiple cytokines with seemingly identical responses (cross-talk). A possible consequence of this functional overlap is the observation that 1 factor may frequently functionally replace another factor altogether or at least partially compensate for the lack of another factor. Since most cytokines have ubiquitous biological activities, their physiologic significance as normal regulators of physiology is often difficult to assess.
Gene function studies in experimental transgenic knock-out animals in which a cytokine gene has been functionally inactivated by gene targeting are very important in cytokine-research since, unlike in vitro studies, they provide information about the true in vivo functions of a given cytokine by highlighting the effects of their absence. In many instances these studies have shown that null mutations of particular cytokine genes do not have the effects in vivo expected from their activities in vitro.
Cytokines show stimulating or inhibitory activities and synergize or antagonize the actions of other factors. 1 sole Cytokine elicits reactions under certain circumstances that are the reverse of those shown under other circumstances. The type, the duration, and also the extent of cellular activities induced by a particular cytokine can be influenced considerably by the micro-environment of a cell, depending, for example, on the growth state of the cells (sparse or confluent), the type of neighboring cells, cytokine concentrations, the combination of other cytokines present at the same time, and even on the temporal sequence of several cytokines acting on the same cell. Under such circumstances combinatorial effects thus allow a single cytokine to transmit diverse signals to different subsets of cells.
Although some cytokines are known to share at least some biological effects, the observations that single cells usually show different patterns of gene expression in response to different cytokines can be taken as evidence for the existence of cytokine receptor-specific signal transduction pathways. Shared and different transcriptional activators that transduce a signal from a cytokine receptor to a transcription regulatory element of DNA are involved in these processes such as STAT proteins.
Basic FGF (bFGF) is a strong mitogen for fibroblasts at low concentrations and a chemoattractant at high concentrations. FGFb (FGF-b) has been shown also to be a biphasic regulator of human hepatoblastoma-derived HepG2 cells, depending upon the concentration. Interferon-gamma (IFN-gamma) can stimulate the proliferation of B-cells prestimulated with Anti-IgM, and inhibits the activities of the same cells induced by IL-4 (IL4). On the other hand, IL-4 (Interleukin-4) activates B-cells and promotes their proliferation while inhibiting the effects induced by IL2 in the same cells. The activity of at least two cytokines such as IL1-A (IL1A) & IL1-B (IL1B) is regulated by an endogenous receptor antagonist, the IL1 receptor anagonist (IL1TA). Cytokines, such as TNFA (TNF-A), IFN-gamma (IFN-G), IL-2 (IL2) & IL-4 (IL4), are inhibited by soluble receptors. Cytokines including IL-10 (IL10) and TGF-beta (TGF-B), inhibit other cytokines.
Early Cytokines preactivate cells so that they then can respond to late-acting cytokines. Cytokines induce the synthesis of novel gene products once they have bound to their corresponding. Several of the novel products are themselves cytokines. In addition, there are a variety of biological response modifiers that function as Anti-cytokines.
Cytokine mediators swiftly remote areas of a multicellular organism & multiple target cells can be degraded quickly, One can assume that cytokines play a pivotal role in all sorts of cell-to-cell communication processes although many of the mechanisms of their actions have not yet been elucidated in full detail.
Thorough examination of the physiological effects of the expression of cytokines in complex organisms has shown that these mediators are involved in all systemic reactions of an organism, including the important processes as regulation of immune responses, for example: BCDF(B-cell growth and differentiation factors), BCGF (B-cell growth factors) TRF (T-cell replacing factors), Isotype switching, inflammatory processes, hematopoiesis, and wound healing.
Embryogenesis and organ development inlvolves important mediators called Cytokines. Their activities in these processes may differ from those observed postnatally. Cytokines play a key role in neuroimmunological, neuroendocrinological, and neuroregulatory processes. Cytokines also regulate cell cycle, differentiation, migration, cell survival & cell death, and cell transformation. Viral infectious agents exploit the cytokine repertoire of organisms to evade immune responses of the host. Virus-encoded factors affect the activities of cytokines in at least four different ways: by inhibiting the synthesis and release of cytokines from infected cells; by interfering with the interaction between cytokines and their receptors; by inhibiting signal transmission pathways of cytokines; and by synthesizing virus-encoded cytokines that antagonize the effects of host cytokines mediating antiviral processes. Bacteria and micro-organisms also appear to produce substances with activities resembling those of cytokines and which they utilize to subvert host responses.
Cytokines are rarely related among eachother in their primary sequences. Some appear to have common 3 dimensional features and some of them can be grouped into families. An example is the TNF ligand superfamily members (with the exception of LT-alpha) are type 2 membrane glycoproteins (N-terminus inside) with homology to TNF in the extracellular domain (overall homologies, 20 %). The HBNF family includes members of the group of fibroblast growth factors. The chemokine group which contain diverse factors also have conserved sequence features. Analysis of crystal structures of several cytokines with very little sequence homology has revealed a common overall topology that is not deducible from sequence comparisons.
Cytokine biological activity of is mediated by specific membrane receptors, which are expressed on all cell types known. Cytokine expression is also subject to several regulatory although some receptors are expressed also constitutively.
Cytokine receptor proteins are multi-subunit structures that bind ligands and at the same time possess functions as signal transducers due to their intrinsic tyrosine kinase. Many receptors often share common signal transducing receptor components in the same family, which explains, at least in part, the functional redundancy of cytokines. Cross-communication between different signaling systems allows integration diversity of stimuli, which a cell can be subjected to under varying physiological situations. This and the ubiquitous cellular distribution of certain cytokine receptors have hampered attempts to define critical responsive cell populations and the physiologically important cell-specific functions of cytokines in vivo. Numerous receptors are associated with special signal transducing proteins in the interior of the cell. Receptors bind more than 1 cytokine. Cytokine receptors shown to be converted into soluble binding proteins that regulate ligand access to the cell by specific proteolytic cleavage of receptor ectodomains.
Specific activities of cytokines have been the basis for current concepts of therapeutical intervention, in particular of the treatment of hematopoietic malfunctions and tumor therapy. Applications involve the support of chemo- and radiotherapy, bone marrow transplantation, and general immunostimulation.
Balkwill FR and Balkwill F (editors) Cytokine Molecular Biology: A Practical Approach, Oxford University Press (2000); Balkwill FR (editor) Cytokine Cell Biology: A Practical Approach, 3rd edition, Oxford University Press (2001); Callard RE (editor) Cytokines and B lymphocytes. Academic Press, London, (1991); Dinarello CA et al (editors) The physiological and pathological effects of cytokines. Liss, New York, (1990); Habenicht A (editor) Growth factors, differentiation factors, and cytokines, Springer, Berlin (1990); Nilsen-Hamilton M (editor) Growth factors and development. (Current Topics in Developmental Biology, Vol. 24, Academic Press (1990); Oppenheim J Immunophysiology: The Role of Cells and Cytokines in Immunity and Inflammation, Oxford University Press (1991); Oppenheim J et al (editors) Cytokine Reference: A Compendium of Cytokines and Other Mediators of Host Defense, Academic Press (2000); Ransohoff RM (editor), Cytokines and the CNS, CRC Press (1996); Villinger F et al Comparative sequence analysis of cytokine genes from human and nonhuman primates. Journal of Immunology 155(8): 3946-3954 (1995); Westwick SL et al (editors) Chemotactic cytokines. Plenum Press, New York 1991)
Angiopoietin-1
Angiopoietin-2
Angiopoietin-3
Angiopoietin-4
Angiopoietin-5
angiopoietin-like-1
angiopoietin-like-2
angiopoietin-like-3
angiopoietin-like-4
angiopoietin-like-5
angiopoietin-like-6
angiopoietin-like-7
ANGPT1
ANGPT2
ANGPT3
ANGPT4
ANGPT5
ANGPTL1
ANGPTL2
ANGPTL3
ANGPTL4
ANGPTL5
ANGPTL6
ANGPTL7
angiopoietin-like lipoprotein modulator
Angiopoietin-related growth factor
Angiopoietin-related protein-1
Angiopoietin-related protein-2
Angiopoietin-related protein-4
Angiopoietin-related protein-5
angiopoietins
Angiopoietin X
Angiopoietin Y
Acrp30
gAcrp30
adipocytes
adipocyte-specific secretory protein
adipokines
AdipoQ
adipose Most abundant gene transcript-1
apM1
Apn
C1q/TNF-alpha-related protein 2
C1q/TNF-alpha-related protein
CFU-G
CFU-GM
CFU-M
CTRP
CTRP-2
GBP-28
gelatin-binding protein of 28 kDa
Pref-1
3T3-F442A
ALK3
ALK6
astrocytes
BAMBI
B-cell/myeloid common progenitor
BDGF
BMP1
BMP10
BMP11
BMP12
BMP13
BMP14
BMP15
BMP2
BMP2A
BMP2-alpha
BMP2B
BMP2-beta
BMP3
BMP3b
BMP4
BMP5
BMP6
BMP7
BMP8
BMP8a
BMP8b
BMP9
Bone growth factor
Bone morphogenetic protein-1
Bone morphogenetic protein-10
Bone morphogenetic protein-11
Bone morphogenetic protein-12
Bone morphogenetic protein-13
Bone morphogenetic protein-14
Bone morphogenetic protein-15
Bone morphogenetic protein-2
Bone morphogenetic protein-2A
Bone morphogenetic protein-2-alpha
Bone morphogenetic protein-2B
Bone morphogenetic protein-2-beta
Bone morphogenetic protein-3
Bone morphogenetic protein-3b
Bone morphogenetic protein-4
Bone morphogenetic protein-5
Bone morphogenetic protein-6
Bone morphogenetic protein-7
Bone morphogenetic protein-8
Bone morphogenetic protein-8a
Bone morphogenetic protein-8b
Bone morphogenetic protein-9
Bone morphogenetic proteins
BP10
BRK-1
CDMP
cementoblasts
Cerberus
CHL
DAF4
DAN
DIAP
dpp
Drosophila melanogaster 60A
DVR
DVR-4
DVR-6
Ectodin
EHZF
GDF1
GDF9
flt
flt-1
flt-2
flt-3
flt-3L
flt-3 ligand
flt-4
flt-4L
flt-4 ligand
IL
ILA
IL1
IL1A
IL1-alpha
IL1B
IL1-beta
IL1-beta Convertase
IL1-beta Convertase-related-2
IL1-beta Convertase-related-3
IL1-beta converting enzyme
IL1-beta-converting enzyme-related proteases
IL1-delta
IL1-epsilon
IL1F1
IL1F2
IL1F3
IL1F4
IL1F5
IL1F6
IL1F7
IL1F7b
IL1F8
IL1F9
IL1F10
IL1 family
IL1 family member 1
IL1 family member 2
IL1 family member 3
IL1 family member 4
IL1 family member 5
IL1 family member 6
IL1 family member 7
IL1 family member 7b
IL1 family member 8
IL1 family member 9
IL1 family member 10
IL1-gamma
IL1H
IL1H1
IL1H2
IL1H3
IL1H4
IL1 homolog-1
IL1 homolog-2
IL1 homolog-3
IL1 homolog-4
IL1-HY1
IL1-HY2
IL1-inducible 26k factor
IL1 inhibitor
IL1 inhibitory activity
IL1 inhibitory protein
IL1k
IL1-L1
IL1-like protein-1
IL1R
IL1R1
IL1R2
IL1RA
IL1ra
IL1ra1
IL1ra2
IL1ra3
IL1raBF
IL1RAcP
IL1RAcPL
IL1R-alpha
IL1RAP
IL1RAPL
IL1RAPL1
IL1RAPL2
IL1RB
IL1R-beta
IL1 receptor accessory protein
IL1 receptor accessory protein-like
IL1 receptor accessory protein-like-1
IL1 receptor accessory protein-like-2
IL1 receptor antagonist
IL1 receptor antagonist-1
IL1 receptor antagonist-2
IL1 receptor antagonist-3
IL1 receptor antagonist protein
IL1 receptor-associated kinase
IL1 receptor-associated kinase-1
IL1 receptor-associated kinase-1b
IL1 receptor-associated kinase-1c
IL1 receptor-associated kinase-1S
IL1 receptor-associated kinase-2
IL1 receptor-associated kinase-4
IL1 receptor-associated kinase M
IL1 receptor-associated kinase W
IL1 receptor-like-1
IL1 receptor R8
IL1 receptor-related protein
IL1 receptor-related protein-1
IL1 receptor-related protein-2
IL1-related protein-1
IL1-related protein-2
IL1-related protein-3
IL1RL-1
IL1RL-1 ligand
IL1RN
IL1RP1
IL1RP2
IL1RP3
IL1Rrp
IL1Rrp2
IL1 suppressor factor
IL1ss
IL2
IL2 dimers
IL2 enhancing factor
IL2-inducible T-cell kinase
IL2-LAK therapy
IL2R-alpha chain inhibitory activity
IL2 receptor inducing factor
IL2-RIF
IL2R/p55 inducing factor
IL3
IL3-alpha
IL3-beta
IL3-IAP
IL3 inhibitor p16
IL3-LA
IL3-like activity
IL3 receptor affinity converter
IL4
IL4BP
IL4-delta-2
IL4 induced nuclear-activating factor
IL4 induced secreted protein
IL4-NAF
IL4-STAT
IL5
IL6
IL6DBP
IL6-Delta-4
IL6-dependent DNA binding protein
IL6 G-CSF related factor
IL6 inducing factor
IL6RE
IL6 receptor soluble urinary protein
IL6 receptor superantagonists
IL6 responsive element
IL6R-SUP
IL6 signal transducer
IL6ST
IL6 type cytokines
IL7
IL7-associated pre-pro-B-cell growth stimulating factor
IL8
IL8 converting enzyme
IL8nL
IL8X
IL9
IL10
IL10C
IL10D
IL10 family
IL10-related T-cell derived inducible factor
IL11
IL11Ralpha-locus chemokine
IL12
IL12A
IL12B
IL12 family
IL12-p35
IL12-p40
IL12-p70
IL12-p70 inhibitory activity
IL12-p80
IL13
IL13BP
IL14
L15
IL15RA
IL16
IL17
IL17A
IL17B
IL17C
IL17D
IL17E
IL17F
IL17 receptor homolog-1
IL17 receptor-like gene
IL17Rh1
IL17RL
IL17-secreting T-cells
IL17(+) T-helper cells
L18
IL18 binding protein
IL18BP
IL18BPa
IL18BPb
IL18BPc
IL18BPd
IL18RAP
IL18 receptor accessory protein
IL18 type 2
IL19
IL20
IL21
IL22
IL22 binding protein
IL22BP
IL23
IL23-p19
IL23-p40
IL24
IL25
IL26
L27
IL27p28
IL28A
IL28B
IL29
IL30
IL31
IL32
IL32-alpha
IL32-beta
IL32-gamma
IL32-delta
IL33
IL-B4
Interleukin-1
Interleukin-1-alpha
Interleukin-1-beta
Interleukin-1-beta converting enzyme
Interleukin-1-delta
Interleukin-1-epsilon
nterleukin-1 family member 5
Interleukin-1 family member 6
nterleukin-1 family member 7
Interleukin-1 family member 8
Interleukin-1 family member 9
Interleukin-1 family member 10
Interleukin-1 Inhibitor
Interleukin-1 receptor antagonist
Interleukin-1ss
Interleukin-2
Interleukin-3
Interleukin-4
Interleukin-5
Interleukin-6
nterleukin-7
Interleukin-8
interleukin-8nL
interleukin-8X
Interleukin-9
Interleukin-10
Interleukin-10C
Interleukin-10D
Interleukin-11
interleukin-11 receptor alpha-locus chemokine
nterleukin-12
Interleukin-13
Interleukin-13 binding protein
Interleukin-14
Interleukin-15
Interleukin-16
Interleukin-17
Interleukin-17A
Interleukin-17B
Interleukin-17C
Interleukin-17E
Interleukin-17F
Interleukin-18
Interleukin-19
Interleukin-20
Interleukin-21
Interleukin-22
Interleukin-23
Interleukin-24
Interleukin-25
Interleukin-26
Interleukin-27
Interleukin-28A
Interleukin-28B
Interleukin-29
Interleukin-30
Interleukin-31
Interleukin-32
Interleukin-33
Interleukin-beta
Interleukin B
Interleukin enhancer binding factor
nterleukin for Da cells
Interleukin-hemopoietin-1
Interleukin-HP1
Interleukin-hybridoma/plasmacytoma-1
Interleukins
Interleukin T
IFN
IFN-alpha
IFN-alpha-1
IFN-alpha-2
IFN-alpha-2a
IFN-alpha-2b
IFN-alpha-4
IFN-alpha II1
IFN-alpha Con1
IFN-alphaLe
IFN-alphaLy
IFN-beta
IFN-beta-2
IFN-beta inducing factor
IFN-c
IFN-delta
IFN-gamma
IFN-gamma inducible secretoglobin
IFN-gamma inducible protein 10
IFN-gamma inducing factor
IFN-gamma regulated human melanoma-associated antigen
IFN-inducible protein 10
IFN-kappa
IFNL1
IFNL2
IFNL3
IFN-lambda-1
IFN-lambda-2
IFN-lambda-3
IFN-omega
IFN-tau
IFN-zeta
Interferon-alpha
Interferon-beta
Interferon-beta-2
Interferon consensus sequence binding protein
Interferon consensus sequence binding protein-1
Interferon-delta
Interferon-gamma
interferon-gamma-inducible protein-9
Interferon-gamma inducing factor
interferon-induced protein 16
Interferon-induced protein 17
interferon-induced transmembrane protein 1
Interferon-inducible-10
Interferon-inducible 78 kDa protein
Interferon-inducible protein-10
Interferon-inducible protein 9-27
Interferon-inducible T-cell alpha chemoattractant
Interferon-kappa
Interferon-lambda-1
interferon-lambda-2
interferon-lambda-3
Interferon-omega
interferon-producing killer dendritic cells
Interferon regulatory factor
Interferon regulatory factor-1
Interferon regulatory factor-2
Interferon regulatory factor-3
Interferon regulatory factor-4
interferon regulatory factor-5
Interferon regulatory factor-6
Interferon regulatory factor-7
interferon regulatory factor-8
Interferon regulatory factor-10
interferon-related developmental regulator-1
interferon-related developmental regulator-2
Interferon-related protein
Interferon response sequence
interferon response transcript 1
Interferon-stimulated gene-15
Interferon-stimulated gene factor-1
Interferon-stimulated gene factor-2
Interferon-stimulated gene factor-3
Interferon-stimulated response element
Interferon-tau
Interferon-zeta
Resistin
RELM
RELM-alpha
RELM-beta
RELM-gamma
adipocytes
adipokines
adipose tissue-specific secretory factor
ADSF
FIZZ-1
FIZZ-2
FIZZ-3
Resistin-like molecules
RSTN
TNF
TNFA
TNFAIP2
TNFAIP3
TNFAIP3 interacting protein 1
TNFAIP3 interacting protein 2
TNFAIP4
TNFAIP6
TNFAIP8
TNF-alpha
TNF-alpha convertase
TNF-alpha converting activity
TNF-alpha converting enzyme
TNF-alpha-induced protein 2
TNF-alpha-induced protein 3
TNF-alpha-induced protein 4
TNF-alpha-induced protein 6
TNF-alpha-induced protein 8
TNF-alpha INH
TNF-alpha-inhibiting factor
TNF-alpha inhibitory protein B1
TNF-alpha muteins
TNF-alpha sheddase
TNF and ApoL related leukocyte expressed ligand-1
TNF and ApoL related leukocyte expressed ligand-2
TNFAR
TNFB
TNF-beta
TNF-BF
TNFBP
TNFBP-1
TNF binding protein
TNF binding protein-1
TNF binding protein-2
TNF blocking factor
TNF C
TNF-induced adipose-related protein
TNFIP6
TNF ligand superfamily member 1
TNF ligand superfamily member 2
TNF ligand superfamily member 3
TNF ligand superfamily member 4
TNF ligand superfamily member 5
TNF ligand superfamily member 6
TNF ligand superfamily member 7
TNF ligand superfamily member 8
TNF ligand superfamily member 9
TNF ligand superfamily member 10
TNF ligand superfamily member 11
TNF ligand superfamily member 12
TNF ligand superfamily member 13
TNF ligand superfamily member 13B
TNF ligand superfamily member 14
TNF ligand superfamily member 15
TNF ligand superfamily member 18
TNF ligand superfamily member 19
TNF ligand superfamily member 20
TNF-like-1
TNF-like-1A
TNF-like-2
TNF-like-6
TNF-like weak inducer of apoptosis
TNFL superfamily
TNF-R1-associated death domain protein
TNFR55
TNFR60
TNFR80
TNF receptor apoptosis-mediating protein
TNF receptor-associated protein
TNF receptor-associated protein 1
TNF receptor-associated protein 2
TNF receptor homolog 1
TNF receptor homolog 2
TNF receptor homolog 3
TNF receptor-like-1
TNF receptor-like-2
TNF receptor-like-3
TNF receptor-like-6
TNF receptor superfamily
TNF receptor superfamily member 1A
TNF receptor superfamily member 1B
TNF receptor superfamily member 4
TNF receptor superfamily member 5
TNF receptor superfamily member 6
TNF receptor superfamily member 6b
TNF receptor superfamily member 7
TNF receptor superfamily member 8
TNF receptor superfamily member 9
TNF receptor superfamily member 10A
TNF receptor superfamily member 10B
TNF receptor superfamily member 10C
TNF receptor superfamily member 10D
TNF receptor superfamily member 11A
TNF receptor superfamily member 11B
TNF receptor superfamily member 12
TNF receptor superfamily member 12A
TNF receptor superfamily member 13B
TNF receptor superfamily member 13C
TNF receptor superfamily member 14
TNF receptor superfamily member 15
TNF receptor superfamily member 16
TNF receptor superfamily member 17
TNF receptor superfamily member 18
TNF receptor superfamily member 19
TNF receptor superfamily member 19-like
TNF receptor superfamily member 21
TNF receptor superfamily member 22
TNF receptor superfamily member 23
TNF receptor superfamily member 24
TNF receptor superfamily member 25
TNF receptor superfamily member 26
TNF-related activation protein
TNF-related apoptosis inducing ligand
TNF-related apoptosis inducing ligand-beta
TNF-related apoptosis inducing ligand-gamma
TNF-related death ligand-1
TNF-related death ligand-1-alpha
TNF-related death ligand-1-beta
TNF-related death ligand-1-gamma
TNF-resistance triggering protein
TNFRH1
TNFRH2
TNFRH3
TNFRSF1A
TNFRSF1B
TNFRSF4
TNFRSF5
TNFRSF6
TNFRSF6b
TNFRSF7
TNFRSF8
TNFRSF9
TNFRSF10A
TNFRSF10B
TNFRSF10C
TNFRSF10D
TNFRSF11A
TNFRSF11B
TNFRSF12
TNFRSF12A
TNFRSF13B
TNFRSF13C
TNFRSF14
TNFRSF15
TNFRSF16
TNFRSF17
TNFRSF18
TNFRSF19
TNFRSF19L
TNFRSF21
TNFRSF22
TNFRSF23
TNFRSF24
TNFRSF25
TNFRSF26
TNF-SAM-2
TNF-Selectokine
TNFSF1
TNFSF2
TNFSF3
TNFSF4
TNFSF5
TNFSF6
TNFSF7
TNFSF8
TNFSF9
TNFSF10
TNFSF11
TNFSF12
TNFSF13
TNFSF13B
TNFSF14
TNFSF15
TNFSF18
TNFSF19
TNFSF20
TNF-stimulated genes
Tumor necrosis factor
Tumor necrosis factor-alpha
tumor necrosis factor-alpha-induced protein 2
Tumor necrosis factor-alpha-induced protein 3
Tumor necrosis factor-alpha-induced protein 4
tumor necrosis factor-alpha-induced protein 6
tumor necrosis factor-alpha-induced protein 8
Tumor necrosis factor-alpha inhibitor
tumor necrosis factor-alpha inhibitory protein B1
Tumor necrosis factor-beta
Tumor necrosis factor binding protein-1
Tumor necrosis factor binding protein-2
Tumor necrosis factor binding proteins
Tumor necrosis factor blocking factor
Tumor necrosis factor C
tumor necrosis factor-induced protein 6
Tumor necrosis factor receptor-associated factor-1
Tumor necrosis factor receptor-associated factor-2
Tumor necrosis factor receptor-associated factor-3
Tumor necrosis factor receptor-associated factor-4
Tumor necrosis factor receptor-associated factor-5
Tumor necrosis factor receptor-associated factor-6
Tumor necrosis factor receptor-associated factor-7
Tumor necrosis factor receptor-associated factors
Tumor necrosis factor-related activation induced cytokine
Tumor necrosis factor-stimulated gene sequence-1
Tumor necrosis factor-stimulated gene sequence-6
Tumor necrosis factor-stimulated gene sequence-8
Tumor necrosis factor-stimulated gene sequence-14
Tumor necrosis factor-stimulated gene sequence-21
Tumor necrosis factor-stimulated gene sequence-27
Tumor necrosis factor-stimulated gene sequences
